JP5232062B2 - Chronotherapeutic dosage form - Google Patents

Description

  The present invention relates to a chronotherapeutic dosage form containing a therapeutically effective amount of a drug. The present invention further relates to a method for preparing the preparation and a therapeutic method using the preparation.

  Adjustment of biological rhythm (temporal biology) by medical treatment is called time treatment. Temporal treatment takes into account the individual's biological rhythm in determining the timing of the medication and, in some cases, its amount, to optimize the desired effect of the drug and to minimize undesirable effects. According to experts in this new and constantly evolving field, synchronizing the biorhythm of medication levels and disease activity is common for cardiovascular symptoms such as hypertension, high cholesterol, angina, stroke And playing an increasing role in the management of ischemic heart disease. For example, in humans, postoperative death is most likely at 1 am; peptic ulcer recurs at 2 am; blood pressure is at 3 am; asthma is at 4 am at worst. Hay fever is most painful when waking up, and is most likely to have a heart attack or stroke during the morning hours when blood pressure rises to suit daytime. Rheumatoid arthritis improves during the day, but osteoarthritis worsens. Alcohol is the least toxic to the body at around 5pm, a cocktail hour.

  The first application of chronotherapy was in the 1960s, which was a synthetic corticosteroid tablet (Medrol, Upjohn). According to findings by clinicians, the use of drugs in the morning is more effective and has fewer side effects. Another example of a commercial product that uses chronotherapy is the bronchodilator Uniphyl®, which is a long-acting theophylline formulation manufactured by Purdue Frederick (FDA approved in 1989). Take once a day at dinner to control nighttime asthma symptoms. Uniphyl® peaks blood theophylline levels during difficult morning hours and improves lung function.

  Orally controlled release delivery systems can also pass through the entire small intestine, including the duodenum, jejunum, and ileum, so that when such site-specific delivery is required, the active ingredient should be released directly in the colon. Can do. One way to do this is by applying a coating around the active pharmaceutical formulation core so that the formulation is intact as it passes through the gastric tube. The high acidity of the gastrointestinal tract and the presence of proteolytic enzymes and other enzymes in the gastrointestinal tract create a highly digestive environment that makes it easier for pharmaceutical formulations that do not have any type of resistant resistance to the stomach Disassembled. This degradation generally has a detrimental effect on the sustained release of the active substance. In addition to delaying the release rate of the active substance contained in the tablet core, the pharmaceutical formulations with those coatings may also delay the release of the active ingredient for a desired period of time to delay the dissolution of the active substance core. it can. Examples of drug delivery systems with a coating for delayed release can be found in US Pat. Nos. 4,863,742 (Panoz et al.) And 5,891,474 (Busetti et al.) And EP366 621, EP572 942, and EP629 398. In the delayed release tablets described in each of these documents, the therapeutically active substance core is coated with at least one layer, and possibly several layers of coating, but the layer of coating is applied to the patient's system of active substance in the tablet core. Directly affects the release after a certain period of time.

  As will be appreciated by those skilled in the art, it is possible to provide an oral controlled release delivery system that is adaptable to drug delivery so that the release rate and drug profile in plasma meet the physiological and time therapeutic needs. desirable.

Objects and Summary of the Invention It is an object of the present invention to provide an oral pharmaceutical dosage form that releases a drug into a patient's body at a predetermined time after oral ingestion by the patient.

  A further object of the present invention is to provide an oral pharmaceutical dosage form that delays the release of the drug into the patient's gastrointestinal tract at a predetermined time after ingestion.

  A further object of certain embodiments of the present invention is to provide an oral pharmaceutical dosage form having a core comprising a drug, the core being compression coated with a coating, whereby the dosage form is administered orally to a patient. Drug is released slowly.

  A further object of certain embodiments of the present invention is to provide an oral pharmaceutical dosage form having a core comprising a drug, the core being compression coated with a coating, whereby the drug is administered when the dosage form is orally administered to a patient. Is delayed.

  A further object of certain embodiments of the present invention is to provide dosage forms that allow time-specific administration to a wide range of diseases.

  A further object of certain embodiments of the present invention is to provide a dosage form that allows time-specific administration for diseases such as arthritis, hypertension, or asthma that typically manifests in the early morning in response to circadian rhythms. Is to provide.

  A further object of certain embodiments of the present invention is to provide a dosage form in which the drug is delayed released from the dosage form, and then the drug is sustained released as it passes through the gastrointestinal tract.

  A further object of certain embodiments of the present invention is to provide a compression coated dosage form that has an immediate release layer of the drug that further coats the compression coated core, thereby providing the same dosage form. The same or different drug from the form is delayed released; the core optionally releases the drug continuously as the dosage form subsequently passes through the gastrointestinal tract.

  A further object of certain embodiments of the present invention is to provide an oral dosage form for site-specific delivery of drugs (eg, to the colon).

  A further object of certain embodiments of the present invention is to develop oral dosage forms that allow programmed release of drugs.

  A further object of certain embodiments of the present invention is to develop oral dosage forms that release the drug pulsatile.

  In accordance with the above objects of the present invention, the present invention relates to an oral dosage form comprising a core containing a therapeutically effective amount of a drug and a compression coating applied to the core, the compression coating being a surface of the core Contains a delayed release agent comprising one or more natural or synthetic gums that are compression coated thereon, thereby allowing release of the drug from the dosage form after oral administration to a mammal (eg, a human patient) of the same dosage form The time is delayed.

  In certain preferred embodiments, the compression coating comprises a mixture (eg, a matrix) of xanthan gum, locust bean gum, and pharmaceutically acceptable carbohydrates such as monosaccharides, disaccharides, polyhydric alcohols, or any combination thereof. contains. In certain preferred embodiments, the core is an immediate release core containing the drug with one or more pharmaceutically acceptable additives.

  The present invention further relates in part to a delayed release oral solid dosage form comprising a core containing a therapeutically effective amount of a drug and a delayed release agent compression coated onto the core, wherein the delayed release agent comprises one or more delayed release agents. Containing natural or synthetic gums, the compression coating delays the release of the drug from the dosage form from about 2 hours to about 18 hours after exposure to the aqueous solution of the dosage form.

  The present invention further relates, in part, to a delayed release oral solid dosage form comprising a core containing a therapeutically effective amount of a drug and an agglimerated delayed release agent compression coated onto the core. The release agent contains, for example, a gum selected from homopolysaccharides, heteropolysaccharides, and mixtures of homopolysaccharides and heteropolysaccharides with pharmaceutically acceptable additives, and the compression coating releases the drug from the dosage form. Is delayed for a predetermined time after exposure to an aqueous solution of the same dosage form.

  The invention further relates in part to a delayed release oral solid dosage form comprising a core containing a therapeutically effective amount of an agent and a disintegrant and a delayed release agent compression coated on the core, the delayed release agent comprising: Containing one or more natural or synthetic gums, the compression coating delays the release of the drug from the dosage form for a predetermined time after exposure to the aqueous solution of the dosage form, and the disintegrant is in an effective amount Contained in the core, thereby releasing at least about 50% of the same drug into the aqueous solution within one hour after the predetermined time.

  The invention further relates in part to a delayed release oral solid tablet comprising a tablet core containing a therapeutically effective amount of a drug and a delayed release agent compression coated onto the core, the delayed release agent comprising one or more delayed release agents. Containing natural or synthetic gums, the gums containing from about 6.5% to about 83% by weight of the tablet, the compression coating exposing the release of the drug from the dosage form to an aqueous solution of the dosage form Later, it is delayed from about 2 hours to about 18 hours.

  The invention further relates to a time-treated delayed release oral solid dosage form for a low dose drug comprising a core containing from about 0.01 mg to about 40 mg of drug and a delayed release agent compression coated on the core. The delayed release agent contains one or more natural or synthetic gums, the compression coating contains about 75 to about 94% by weight of the oral solid dosage form, and the ratio of gum in the core and compression coating is about 1 : 0.37 to about 1: 5 (weight ratio), and the compression coating delays the release of the drug from the dosage form from about 2 hours to about 18 hours after exposure to the aqueous solution of the dosage form.

  In addition, the present invention includes, in part, a time-treatment delayed release oral solid for relatively high dose drugs comprising a core containing from about 41 mg to about 300 mg of drug and a delayed release agent compression coated on the core. For the dosage form, the delayed release agent contains one or more natural or synthetic gums, and the ratio of gum in the core to the compression coating is from about 1: 0.3 to about 1: 3 (weight ratio). The total weight of the oral solid dosage form is from about 500 mg to about 1500 mg, and the compression coating delays the release of the drug from the dosage form from about 2 hours to about 18 hours after exposure to the aqueous solution of the dosage form .

  The present invention further relates, in part, to a method for preparing a time-treated oral solid dosage form of a drug, wherein the method prepares a core containing a therapeutically effective amount of the drug and about 5 to about 20% by weight of the disintegrant of the core. Preparation of granules of delayed release agent containing one or more natural or synthetic gums, compression coating of the granules to the core, the compression coating exposing the release of the drug to an aqueous solution of the dosage form Delay about 2 hours to about 18 hours later. In certain preferred embodiments, the method prepares delayed release granules by wet granulation by granulating one or more natural or synthetic gums with at least one pharmaceutically acceptable additive and resulting granules. Further drying to obtain bulk particles of delayed release agent. In certain embodiments, the method further includes granulating the glucocorticosteroid, the disintegrant, and a pharmaceutically acceptable inert diluent prior to the compression coating step.

  In one preferred embodiment, the superintegrant is mixed into the core in an amount effective to release at least about 50% of the drug into the aqueous solution within one hour after the delayed release time ends.

  The present invention further relates to methods of treatment utilizing the formulations disclosed herein.

  In certain embodiments, the oral dosage form provides a lag time of about 2 to about 18 hours (delays the release of the drug) after oral administration (eg, to a human subject or patient).

  In certain preferred embodiments, the oral dosage form contains at least about 50% of the drug contained in the core within about 1 hour, preferably in the same core after the end of the lag time provided by the compression coating. At least about 80% of the drug being released is released within about 1 or 2 hours.

  In certain embodiments, the oral dosage forms of the invention provide a lag time of about 5 hours to about 8 hours after oral administration (eg, to a human patient) and release completely from about 8 hours to about 12 hours.

  In certain preferred embodiments, the oral dosage form provides a lag time of about 6 hours to about 7 hours after oral administration of the dosage form and releases completely from about 8 hours to about 9 hours.

  In other preferred embodiments, the oral dosage form provides a lag time of about 6 hours to about 7 hours after oral administration, followed by complete release of the drug in about 7 hours to about 8 hours.

  In yet another embodiment, the formulation provides a lag time of about 9 hours to about 12 hours after oral administration and is fully released in about 11 hours to about 13 hours, preferably about 10 hours after oral administration of the same dosage form. From about 11 hours to about 12 hours, followed by complete release in about 11 hours to about 12 hours.

  In yet another embodiment, the formulation provides a lag time (eg, about 3-12 hours) and releases the drug completely from the dosage form within about 24 hours or (or) after 24 hours.

  For the purposes of the present invention, “delayed release” means that the release of the drug is delayed and that the drug contained in the dosage form is not substantially released from the formulation until after a certain time, eg immediately upon ingestion of the tablet by the patient. Rather, it means that the drug is released into the patient's bloodstream only after a certain time (eg, 4 to 9 hours delay). For the purposes of the present invention, delayed release is synonymous with "definite time delay" or drug release after a delay time, or programmed release.

  For the purposes of the present invention, “sustained release” means that once a drug is released from the formulation, it is released at a controlled rate, so that the therapeutically beneficial blood level of the drug (but less than the toxic level) is released. It is held for a long time from the start of the release, for example, it means that the release proceeds for a certain time (for example, about 4 hours to about 24 hours) from the time point of drug release after the delay time.

  For the purposes of the present invention, “environmental fluid” is intended to include, for example, an aqueous solution (eg, an in vitro dissolution bath) or gastrointestinal fluid.

  As used herein, the term US Pharmacopeia device type III is described, for example, in US Pharmacopeia XXV (2002).

Detailed Description of the Invention The present invention may be used to effect time-delayed release of pharmaceutically active agents, and in some embodiments, to provide controlled release pharmaceutical formulations of pharmaceutically active agents. Often, the drug is delivered for a predetermined time as needed. The formulations of the present invention provide time-delayed release of pharmaceutically active agents and may be useful in the treatment of conditions that are treated through time-delayed drug delivery mechanisms as needed. For example, the formulations of the present invention are useful in the treatment of morning medical conditions such as arthritis, hypertension and asthma, the symptoms of which are generally more severe in the morning when the patient wakes up from sleep, ie symptoms, diseases or other diseases. In order to treat these symptoms, the time-delayed release formulation according to the present invention is administered to the patient before going to bed, and the pharmaceutically active drug is delivered or preferably treated when the patient wakes up. It may have already been delivered (and absorbed from the gastrointestinal tract) from the dosage form to the extent that an effect is obtained, thereby reducing the morning pathology.

  The formulations of the present invention contain a core containing the active agent, and a compression coating covering the core, which contains one or more pharmaceutically acceptable natural or synthetic gums. In certain preferred embodiments, the compression coating is a combination of a heteropolysaccharide gum (eg, xanthan gum) and a homopolysaccharide gum (eg, locust bean gum) with a pharmaceutically acceptable sugar (eg, lactose, dextrose, mannitol, etc.). contains. In certain preferred embodiments, the gum is granulated by wet granulation with an optional sugar to form agglomerated particles including, for example, a mixture of xanthan gum, locust bean gum, and dextrose.

  The purpose of the compression coating of the present invention is to delay the release of the active substance for a predetermined time (referred to in the art as the “delay time”). In certain embodiments, the release of the active agent is delayed or has a delay time of about 2 to about 18 hours after administration of the dosage form.

  The core containing the active substance can be prepared for either immediate release or sustained release of the active substance. Both formulations for immediate and sustained release of the active substance are well known to those skilled in the art.

  In the present invention, when the core containing the active agent is prepared as an immediate release, it can be prepared by any suitable tablet manufacturing method well known to those skilled in the art. For example, a pharmaceutically active agent may be mixed with additives and made into a tablet core using conventional tablet press or conventional wet granulation methods. According to one preferred embodiment of the invention, the core components are dry mixed in a V-mixer and compressed into a tablet core in a rotary tablet press. Alternatively, in some embodiments, the core components can be granulated and dried by wet granulation and then compressed into a tablet core. Preferably, the core should be compressed to a hardness that does not chip or fall apart during further processing (eg, during coating). In certain embodiments, the core can be compressed to a weight of 50 mg, a hardness of 2 to 8, preferably 4 to 8, and most preferably 4-5 kP. Further, the tablet core size should be in the range of 1/8 inch to 5/8 inch, preferably 1/8 inch to 1/2 inch, more preferably 3/16 inch to 1/4 inch.

  In certain embodiments where the core is manufactured without a wet granulation step and the final mixture is compressed into a tablet core, all or some of the additives in the core may contain off-the-shelf direct compression diluents. Good. Examples of these ready-made direct compression diluents include Emcocel® (microcrystalline cellulose, US National Medicinal Products (NF)), Emdex® (dextrates (US National Medicinal Products)), And Tab-Fine® (many direct compression sugars including sucrose, fructose, and dextrose), all sold by Penwest Pharmaceuticals (Patterson, New York). Other direct compression diluents include: anhydrous lactose (Lactose (National Drug Collection)), anhydrous direct tableting (Sheffield Chemical, Union NJ 07083); Elcems® G-250 ( Powdered Cellulose (US National Medicinal Products) (Degussa, D-600 Frankfurt (Main) Germany); Fast-Flo Lactose® (Lactose (US National Medicinal Products), spray-dried) (Foremost Whey Produsts, Banaboo, WI 53913); Maltrin® (bulk maltodextrin) (Grain Processing, Muscatine, IA 52761); Neosorb 60® (sorbitol (US National Medicinal Products), direct compression) (Roquet, 645 5th Ave New York, NY 10022); Nu-Tab® (compressible sugar (National Drug Collection)) (Ingredient Technology, Pensauken, NJ 08110); Polyplasdone XL® (Crospovidone) American National Medicine Collection), Cross-linked polyvinyl pyrrolidone (GAF, New York, NY 10020); Primojel (R) (sodium starch glycollate (National Medicines), carboxymethyl starch) (Generichem, Little Falls, NJ07424); Solka Floc (Registered trademark) (cotton cellulose) (Penwest Pharmaceuticals, Patterson NY 10512); Spray-dried lactose (registered trademark) (Lactose (National Drug Collection), spray-dried product) (Foremost Whey Products, Baraboo, WI 53913, And DMV, Vehgel, Holland); and Sta-Rx 1500® (Starch 1500) (pregelatinized starch (US National Pharmaceuticals), compressibility) (Colorcon, West Point, PA 19486). In one embodiment, the directly compressible inert diluent used in the core of the present invention is US Pat. No. 5,585,115 (December 17, 1996, “Pharmaceutical Excipient with Improved Compressibility”). Having Impr oved Compressibility))), which is an augmented microcrystalline cellulose, which is incorporated herein by reference in its entirety. The enhanced microcrystalline cellulose described therein is sold by Penwest Pharmaceuticals under the trade name Prosolv®. PROSOLV SMCC 50 is a silicified microcrystalline cellulose. This particular grade has a median particle size (by sieving analysis) of about 50 μm. PROSOLV SMCC 90 is a silicified microcrystalline cellulose. This grade has a median particle size (by sieve analysis) of about 90 μm.

  Alternatively, in certain embodiments, the core containing the active agent can be prepared as a sustained release core for sustained release of the active agent. When preparing a core containing an active agent as a sustained release, the core can be prepared in a number of ways known in the art. For example, the active agent is mixed into a sustained release matrix and then compressed into the core, or the sustained release agent is coated onto the immediate release core to provide sustained release of the active agent, or the compressed sustained release matrix and core The above sustained release coating can be used in combination. In addition, it may have a spherical material containing an active agent, or a sustained release coating, and multiparticlates containing the active agent may be compressed with binders and other additives as needed to form a sustained release core. .

  When the core of the present invention contains a sustained release matrix, the matrix formulation is generally prepared using standard methods well known in the art. In general, they are prepared by dry mixing the sustained release agent, diluent, active substance, and other additives as required, and then granulating the mixture until suitable granules are obtained. Granulation is performed by methods well known in the art. In general, in wet granulation, wet granules are dried in a fluid bed dryer, sieved and pulverized to a suitable size. A lubricant is mixed with the dried granules to obtain the final core formulation.

  Applicant's U.S. Patent Nos. 4,994,276; 5,128,143; 5,135,757; 5,455,046; 5,512,297; 5,554,387; 5,667,801; 5,846,563; 5,773,025; 6,048,548; (All of which are hereby incorporated by reference), as reported by the applicant, gelling agents such as synergistic heterodisperse polysaccharides (eg heteropolysaccharides such as xanthan gum) (preferably the same heteropolysaccharides). Controlled release additives containing polysaccharide gums (eg together with locust bean gum) that can form crosslinks with orally via direct compression after addition of drug and lubricant powder, conventional wet granulation, or a combination of the two It can be processed into a solid dosage form. These systems (controlled release additives) are sold by Penwest Pharmaceuticals, Inc. (Patterson, N.Y.), the assignee of the present invention, under the trade name TIMERx®.

  In embodiments of the present invention where the core provides sustained release of the active agent, the core contains a sustained release matrix as disclosed in Applicants' above patent. For example, in one embodiment of the invention, in addition to the active agent, the core comprises a sustained release additive comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of forming a cross-linked structure with the heteropolysaccharide when exposed to an environmental liquid. And an inert pharmaceutical diluent. Preferably the ratio of heteropolysaccharide gum to homopolysaccharide gum is from about 1: 3 to about 3: 1 and the ratio of active agent to gelling agent is preferably from about 1: 3 to about 1: 8. The resulting core provides a therapeutically effective blood level of the active substance, preferably for at least about 4 hours, and in some preferred embodiments for about 24 hours. In certain preferred embodiments, the sustained release additive further comprises an effective amount of a pharmaceutically acceptable ionizable gel strength enhancer as described below, and when the core is exposed to an environmental liquid, the active agent is Sustained release. The sustained release additive (with or without optional ionizable gel strength enhancer) can be further modified by the introduction of a hydrophobic substance that delays gum hydration without degrading the hydrophilic matrix. Also good. Further, in certain embodiments, sustained release additives can be modified to provide a two-phase or multi-phase release profile of the active agent by including a pharmaceutically acceptable surfactant or wetting agent in the core. Alternatively, the sustained release additive contains only one of the above gums. In yet another embodiment, the sustained release additive contains another pharmaceutically acceptable gum.

  In addition to the above, other sustained release materials may be used in the sustained release matrix core of the formulations of the present invention. Non-limiting lists of suitable sustained release materials that may be included in the sustained release matrix according to the present invention include hydrophilic and / or hydrophobic materials (eg, sustained release polymer gums, acrylic resins, protein derivatives, waxes, Shellac), and oils (eg, hardened castor oil, hardened vegetable oil). Preferred sustained release polymers include alkyl celluloses such as ethyl cellulose, acrylic and methacrylic acid polymers and copolymers; and cellulose ethers, particularly hydroxyalkyl cellulose (especially hydroxypropylmethylcellulose) and carboxyalkylcellulose. Preferred waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid, and stearyl alcohol). In certain embodiments, a mixture of any of the above sustained release agents is used in the core matrix. However, any pharmaceutically acceptable hydrophobic or hydrophilic sustained release material capable of sustained release of the active agent may be used in accordance with the present invention.

  Alternatively, in certain embodiments of the invention, sustained release of the active agent is achieved by using an immediate release core (as described above) having a sufficient amount of hydrophobic coating to provide sustained release of the active agent from the immediate release core. The core may be prepared such that The hydrophobic coating may be applied to the core using methods and techniques well known to those skilled in the art. Examples of suitable coating equipment include fluid bed coaters, pan coaters and the like. Examples of hydrophobic materials that may be used in these hydrophobic coatings include, for example, alkyl cellulose (eg, ethyl cellulose), copolymers of acrylic acid and methacrylic acid esters, waxes, shellac, zein, hydrogenated vegetable oils, mixtures thereof, and the like. is there.

  In addition, a sustained release matrix and a sustained release coating may be used in combination to prepare the core for sustained release of the active agent. Sustained release cores (eg, sustained release matrices, sustained release coatings, or combinations thereof) and immediate release cores are also suitable amounts of additional additives, such as lubricants, binders, granulation aids customary in the pharmaceutical arts, Diluents, colorants, flavoring agents, and glidants may be included.

  Specific examples of pharmaceutically acceptable diluents and additives that may be used to prepare the core are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), which is incorporated herein by reference. .

  In certain preferred embodiments, the oral dosage form contains one or more disintegrants (preferably mixed with the core). When those drugs are contained in the core, the release rate of the drug (after the first delay caused by the compression coating) is an imimiate pulse effect. In certain embodiments, a controlled profile may be created in the absence of a disintegrant. Suitable disintegrants are known to those skilled in the art and include, for example, sodium starch glycolate (sold as Explotab® by Penwest Pharmaceuticals).

  The mechanism of disintegration is based on disintegrant swelling, wicking, and deformation. When the compressed tablet is placed in an aqueous solution, it quickly absorbs moisture, and the tablet disintegrates quickly due to swelling of the disintegrant. In certain embodiments where the therapeutically active agent is prepared for immediate release, when the disintegrant is present in the tablet core, the release rate of the active agent is an immediate pulse effect. In certain embodiments where the therapeutically active agent is prepared for immediate release, a controlled profile may be created if no disintegrant is present.

  Examples of those disintegrants for use in the present invention include, for example, starch, veegum, crospovidone, cellulose, kaolin, microcrystalline cellulose (eg Avicel PH101 and PH102), cross-linked polyvinyl pyrrolidone (eg Kollidon CL) , And their mixtures. In certain preferred embodiments, the disintegrant is a highly disintegrant such as croscarmellose sodium, crospovidone, cross-linked carboxymethylcellulose, sodium starch glycolate, and mixtures thereof. Advanced disintegrants can be introduced at lower levels than normal disintegrants to increase the water content. Highly disintegrants with trade names for use in the present invention include Ac-Di-Sol (R), Primojel (R), Explotab (R), and Crospovidone (R).

  In certain embodiments, the core of the present invention includes a wicking agent in addition to or in place of the disintegrant. If necessary, a wicking agent (for example, microcrystalline cellulose) such as a substance already described as a disintegrating agent may be included to increase the rate of moisture absorption. Other materials suitable to act as wicking agents include, but are not limited to: colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate , Low molecular weight polyvinyl pyrrolidone, m-pyrrole, bentonite, magnesium aluminum silicate, polyester, polyethylene, and mixtures thereof.

  In certain embodiments, one or more disintegrants are included in the core in an amount of about 5 to about 20 weight percent, preferably about 6 to about 10 weight percent, and most preferably about 8 weight percent of the core. With respect to the total tablet weight (eg, core and compression coating), one or more disintegrants in the core is about 0.1 to about 5 weight percent, preferably about 0.3 to about 2 weight percent of the tablet (whole formulation). Contained in percentage amounts.

  According to the invention, the core containing the active substance is completely or substantially surrounded by a compression coating. The compression coating preferably delays the release of the pharmaceutically active agent for a predetermined time, which time depends on the coating formulation and the coating layer thickness. A suitable time for release of the active ingredient can be determined prior to preparation of the formulation, applying a suitable thickness and composition of the coating, followed by a desired time delay before release of the active ingredient, and a delay time. Formulations can be designed to achieve a desired release rate of the active ingredient.

  Preferably, the compression coating contains a natural or synthetic gum that functions as a gelling agent so that when the compression-coated tablet is exposed to an environmental liquid (eg water or gastrointestinal fluid), the core is surrounded by the gel, The drug is released after the environmental liquid diffuses through the compression coating, the drug dissolves in the environmental liquid, and the dissolved drug dissolves in the liquid surrounding the compression coated tablet.

  In certain embodiments, gums for use in compression coatings include, but are not limited to, heteropolysaccharides such as xanthan gum, homopolysaccharides such as locust bean gum, galactan, mannan, vegetable gums such as alginate, Indian gum, pectin, agar, tragacanth, acacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums (eg hydrocolloids), and mixtures of any of the above. Additional examples of specific gums that may be useful in the compression coatings of the present invention include, but are not limited to: Acacia yak, salai guggal, indian bodellum, copaiba gum, agi, cambi gum, Enterolobium cyclocarpum, mastic Gum, benzoin gum, sandalak, gambier gum, butea frondosa (Flame of Forest Gum), myrrh, konjac mannan, guar gum, welan gum, gellan gum, tara gum, locust bean gum, carrageenan gum, glucomannan, galactan gum, alginic acid Sodium, tragacanth, chitosan, xanthan gum, deacetylated xanthan gum, pectin, polypectin sodium, gluten, indian gum, tamarind gum, ghatti gum, Accaroid / Yacca / Red gum, danmar gum, juniper gum, ester gum, ipil-ipil seed gum, gum talha (acacia seyal) And cultured plant cell gums (including those of the following types of plants: acacia, actinidia, aptenia, carbobrotus, chickorium, cucumis, glycine, hibiscus, hordeum, letuca, tomato (lycopersicon), apple (malus), coconut (Medicago), mesembryanthemum, oryza, panicum, phalaris, phleum, poliathus, polycarbophil, sida, solanum, trifoella, trigonella, Afzelia africana seed gum, Treculia africana gum, detarium gum gum), carob gum, Prosopis africana gum, Colocassia esulenta gum, Hakea gibbosa gum, khaya gum, scleroglucan, corn, mixtures of any of the above.

  In certain particularly preferred embodiments, the compression coating contains a heteropolysaccharide (eg, xanthan gum), a homopolysaccharide (eg, locust bean gum), or a mixture of one or more heteropolysaccharides and one or more homopolysaccharides. Heterodisperse additives already disclosed as sustained release tablet matrices in Applicants' U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757 may be utilized in the compression coatings of the present invention. For example, in certain embodiments of the invention, both synergistic hetero- and homopolysaccharide gelling agents, such as a combination of two or more polysaccharide gums, are more viscous than would be expected from either of the gums alone. Faster hydration, resulting gels are formed faster and harder may be used in the compression coating of the present invention.

  The term “heteropolysaccharide” used in the present invention is defined as a water-soluble polysaccharide containing two or more types of sugar units, and the heteropolysaccharide has a branched or helical structure and has excellent water-wicking properties. And has a very high thickening.

A particularly preferred heteropolysaccharide is xanthan gum, which is a high molecular weight (> 10 ⁶ ) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives of xanthan gum, such as deacylated xanthan gum, carboxymethyl ether, and propylene glycol esters.

  Among the homopolysaccharides used in the present invention, those that can form a crosslinked structure with a heteropolysaccharide include galactomannans, that is, polysaccharides composed only of mannose and galactose. The possible mechanism of interaction between galactomannan and heteropolysaccharide is related to the interaction between the helical region of heteropolysaccharide and the unsubstituted mannose region of galactomannan. It has been shown that galactomannans with a higher proportion of unsubstituted mannose regions have higher interactions with heteropolysaccharides. Accordingly, locust bean gum with a higher ratio of mannose to galactose is particularly preferred compared to other galactomannans (eg guar gum and hydroxypropyl guar gum).

  In certain preferred embodiments, the heteropolysaccharide comprises about 1 to about 50 weight percent of the compression coating and the homopolysaccharide material comprises about 50 to about 1 weight percent of the compression coating. In certain preferred embodiments, the ratio of heteropolysaccharide to homopolysaccharide material is about 1: 3 to 3: 1, preferably about 2: 3 to 3: 2, or 1: 1.

  In certain preferred embodiments, the compression coating contains about 5 to about 70 weight percent or more hydrophilic material (eg, gum). In certain preferred embodiments of the present invention, the higher the percentage of gum in the compression coating, the longer the delay or “delay time” of active agent release.

  In certain embodiments, the percentage of gum in the compression coating correlates with delayed release of the active agent, which is not dependent on pH. For example, in certain preferred embodiments, when the compression coating is less than about 25% gum (preferably containing about 5 to about 15% gum), delayed release is greater than about 25% gum (eg, 30, 40, Or more independent of pH than compression coatings containing 50% gum).

  In certain preferred embodiments, the compression coating also includes pharmaceutically acceptable additives such as sugars, such as monosaccharides, disaccharides, or polyhydric alcohols, and / or mixtures of any of the above, or microcrystalline cellulose or starch. Containing. Examples of suitable such additives include sucrose, dextrose, lactose, fructose, xylitol, sorbitol, mannitol, starch, mixtures thereof and the like. In certain embodiments, it is preferred that soluble pharmaceutical additives such as lactose, dextrose, sucrose, mannitol, or mixtures thereof are included in the material used for the compression coating. In one preferred embodiment, the gum is granulated by wet granulation with a pharmaceutically acceptable additive and then used as a compression coating on the surface of the inner core of the present invention. The compression coating may contain, for example, up to about 95% by weight pharmaceutically acceptable additives.

  In certain embodiments, the amount of gum contained in the compression coating is from about 1 weight percent to about 90 weight percent, preferably from about 6.5 weight percent to about 83 weight percent of the total tablet.

  In some embodiments, the components of the compression (delayed release) coating can be dry mixed without using a wet granulation step. When a mixture is produced without a wet granulation step and the final mixture is compression coated onto a shaped tablet core, the pharmaceutically acceptable additive is fully compressible with all or part of the pharmaceutically acceptable additive. An acceptable product should be provided. The nature and properties of certain additive systems prepared in accordance with the present invention will depend, in part, on individual properties related to polymer solubility (eg, for homopolysaccharide and heteropolysaccharide components), glass transition temperatures, etc., as well as dissolution Modification of the liquid-additive interaction may depend on the interaction between another homopolysaccharide and heteropolysaccharide, and between the homopolysaccharide and heteropolysaccharide and an inactive sugar component.

  In certain embodiments of the invention in which the compression coating contains heteropolysaccharides, homopolysaccharides, or both, the release modifiers are compression coated as described in Applicants' previous patents regarding the use of those materials in sustained release matrices. Can also be used. Their release modifiers and off-the-shelf additives (Applicants' U.S. Patent Nos. 5,455,046; 5,512,297; 5,554,387; 5,677,801; 5,846,563; 5,773,025; 6,048,548; 5,662,933; 5,958,456; 6,039,980) may be used in the compression coating of the present invention.

  Thus, for example, the release modifier may contain an ionizable gel strength enhancer. The ionizable gel strength enhancer used as needed in connection with the present invention may be a unit price or a polyvalent metal cation. Preferred salts are inorganic salts, which include sulfates, chlorides, borates, bromides, citrates, acetates, lactates of various alkali metals and / or alkalinity metals. Specific examples of suitable ionizable gel strength enhancers include: calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride. Sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, and sodium fluoride. Multivalent metal cations may be used. However, the preferred ionizable gel strength enhancer is divalent. Particularly preferred salts are calcium sulfate and sodium chloride. The ionizable gel strength enhancer of the present invention is added in an amount effective to obtain the desired enhanced gel strength by cross-linking gelling agents (eg, heteropolysaccharides and homopolysaccharide gums). In another embodiment, the ionizable gel strength enhancing agent is added to the delayed release additive of the present invention in an amount of about 1 to about 20% by weight of the delayed release additive and 0.5 to about 16 of the final dosage form. Contained in an amount of% by weight. In some embodiments, the inclusion of an ionizable gel strength enhancing agent not only delays the release of the active agent, but also provides a sustained release of the active agent.

  In certain embodiments of the present invention, the (delayed release) compression coating coated on the core has from about 1 to about 90 weight percent gelling agent (containing heteropolysaccharide and homopolysaccharide gum), from about 0 to about 20 weight percent. An ionizable gel strength enhancer, and from about 10 to about 95 weight percent of a pharmaceutically acceptable additive. In other embodiments, the compression coating material comprises about 5 to about 75 percent gelling agent (gum), about 0 to about 15 percent ionizable gel strength enhancer, and about 30 to about 95 percent pharmaceutically acceptable. Containing additives such as inert diluents. In yet another embodiment, the compression coating material comprises about 7.5 to about 50 percent gelling agent, about 0 to about 10 percent ionizable gel strength enhancer, and about 30 to about 95 percent pharmaceutically acceptable. Containing additives.

  Surfactants that may be used in the present invention generally include pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphiphilic / amphophilic) surfactants, and nonionics. There is an ionic surfactant. Suitable pharmaceutically acceptable ionic surfactants include, for example: monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates. Fatty acid-polypeptide condensates, sulfate esters, alkyl sulfates (including sodium lauryl sulfate (SLS)), ethoxylated alkyl sulfates, ester-linked sulfonates (including sodium doxate or dioctyl sodium succinate (DSS)), Alpha olefin sulfonates and phosphorylated ethoxylated alcohols.

  Suitable pharmaceutically acceptable cationic surfactants include, for example, monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium compounds, amidoamines, and amine imides.

  Suitable pharmaceutically acceptable amphoteric (amphiphilic / amphophilic) surfactants include, for example, N-substituted alkylamides, N-alkylbetaines, sulfobetaines, and N-alkyl β-aminopropionates ( aminoproprionates).

  Other surfactants suitable for use in connection with the present invention are polyethylene glycols as esters or ethers. Examples are polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid derived from castor oil, or polyethoxylated fatty acid derived from hydrogenated castor oil. Commercially available surfactants that can be used are known under the trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emerest 2675, Lipal 395, and PEG 3350.

  Other pharmaceutically acceptable release modifiers that may be added in suitable amounts for specific ability to change the dissolution rate include, for example: stearic acid, metal stearate, stearyl alcohol, hydrogenated cottonseed oil , Sodium chloride, and certain disintegrants described below.

  The amount of these release modifiers used depends on the release characteristics and the nature of the substance required. In delayed release formulations according to the present invention, the level of release modifier used may be from about 0.1 to about 25%, preferably from about 0.5 to about 10% by weight of the total composition.

  In certain other embodiments of the present invention, the compression coating includes a pH adjusting agent. The pH adjusting agent may be included in the compression coating from about 1% to about 10% by weight of the final dosage form. In preferred embodiments, the pH adjusting agent is an organic acid such as citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, or lactic acid.

  In certain preferred embodiments, an aqueous environmental solution (such as water surrounding the dosage form or gastrointestinal fluid) diffuses through the compression coating of the dosage form, releasing the drug upon core hydration and drug dissolution, which is then Can pass into the surrounding liquid.

  In certain preferred embodiments, the delayed release (delay time) of the drug is altered by increasing the thickness of the compression coating (increasing delay time) or decreasing the thickness of the compression coating (decreasing delay time). Delayed release can also vary, for example, by: changes in the gums contained in the delayed release compression coating (selection of specific gum combinations), pharmaceutically acceptable additives (eg sugars (including polysaccharides) in the compression coating) ) Or a combination of sugars (or polysaccharides)) or free of water (or gastrointestinal fluid) to diffuse through the compression coating (eg matrix) into the inner core (this allows hydration of the inner core) Further substance changes or additions to the compression coating to further delay. In addition, the compression force used to apply the compression coating may be used to vary the release rate of the active ingredient. It is also possible to change the release by adding further granule additives to the compression coating. These components may contain, for example, microcrystalline cellulose, polyvinyl pyrrolidone, polyethylene glycol and the like.

  The delayed release of the drug can further vary by the use of additional coatings between (i) the core and the compression coating; (ii) on the compression coating; or (iii) both between the core and the compression coating and on the compression coating. The coatings may include, for example, hydrophilic polymers (eg, hydroxypropylmethylcellulose) and / or hydrophobic polymers (eg, acrylic polymers, copolymers of acrylic acid and methacrylic acid esters, alkylcelluloses such as ethylcellulose). In such situations, drug release from the dosage form not only occurs when the liquid diffuses through the compression coating, but drug release can also be delayed by further coating erosion described in this paragraph.

  Mixing the compression coating with a hydrophobic substance that slows the hydration of the gum without disrupting the hydrophilic matrix (with or without the above-mentioned modifying substances as required) You may further modify by. This is done in another embodiment of the invention by granulating the delayed release additive with a solution or dispersion of a hydrophobic material and then compression coating the core. The hydrophobic polymer may be selected from: alkyl celluloses such as ethyl cellulose, other hydrophobic cellulose materials, polymers or copolymers derived from acrylic acid or methacrylic acid esters, copolymers of acrylic acid and methacrylic acid esters, zein, Waxes, shellac, hydrogenated vegetable oils, and other pharmaceutically acceptable hydrophobic substances well known to those skilled in the art. The solvent for the hydrophobic material may be an aqueous or organic solvent, or a mixture thereof. The amount of hydrophobic material mixed with the delayed release additive is an amount effective to delay hydration of the gum without disrupting the hydrophilic matrix produced upon exposure to environmental liquids. In certain preferred embodiments of the present invention, the hydrophobic material is included in the compression coating in an amount of about 1 to about 20 weight percent.

  The compression coating contains suitable amounts of lubricants, binders, granulating aids, diluents, colorants, flavoring agents, and leveling agents that are conventional in the pharmaceutical industry, such as those described below. Also good.

  In a preferred embodiment where the material to be included in the compression coating is off-the-shelf, a gum gelling agent (eg, a mixture of xanthan gum and locust bean gum) and a pharmaceutical additive are combined with or without a release modifier. In addition, an off-the-shelf compression coating product is provided, and the preparer can obtain the desired time-of-treatment dosage form by simply applying the same material onto the core by compression coating. The compression coating may include a physical mixture of gum and soluble additives (eg, compressible sucrose, lactose, dextrose, etc.), but a pharmaceutically acceptable additive (ie, crystalline) sucrose, lactose that does not include the gum mixture. Preferably, it is granulated or agglomerated with dextrose, mannitol, etc. to produce a delayed release additive for use in compression coatings. Granule morphology has certain advantages, including that it can be optimized for flowability and compressibility.

  The gums used in the press coating and optional pharmaceutical additives are preferably prepared according to an agglomeration technique to obtain an acceptable additive product. In wet granulation, a desired amount of a hydrophilic substance (eg, heteropolysaccharide gum and / or homopolysaccharide gum) and an inert diluent are mixed, followed by a wetting agent (eg, water, propylene glycol, glycerol, alcohol, etc.). Add to prepare a wet mass. The wet mass is then dried. The dried mass is then pulverized into granules by conventional equipment. Thereafter, the additive product is ready for use.

  The (preferably) off-the-shelf delayed release additive is preferably flowable and can be compressed directly. Thus, the additive may be compressed directly onto a molded inner core of a therapeutically active pharmaceutical product to produce a coated tablet. A sufficient amount of delayed release coating mixture to uniformly coat onto the shaped tablet core is applied to a tablet on a conventional production scale tablet machine at normal compression pressure, ie, about 2000-1600 pounds per square inch. Turn into. However, the mixture should not be compressed so that its hydration becomes difficult upon subsequent exposure to gastrointestinal fluid.

  The average particle size of the granulated delayed release additive of the present invention ranges from about 50 microns to about 400 microns, preferably from about 185 microns to about 265 microns. The particle size of the granule is not strictly important, an important parameter is that the average particle size of the granule enables the production of a directly compressible additive that coats the pharmaceutically active tablet core. Desired attributes (tap) and bulk density of the granules of the present invention are typically between about 0.3 and about 0.8 g / ml, with an average density of about 0.5 to about 0.7 g / ml.

  The compression coating of the present invention preferably has a uniform fillability over a range of different particle size distributions and is subjected to processing on the shaped tablet core using direct compression following the addition of a lubricant. It is possible.

  In addition to being used for the tablet core (as needed), in one embodiment, one or more pharmaceutically acceptable lubricants are added to the (preferably pre-agglomerated) compression coating material, and then the mixture is It is preferred to compression coat on the surface of the core. Examples of suitable lubricants for use in the cores and compression coatings of the present invention include, but are not limited to, talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate, and the like. Preferably, an effective amount of a generally acceptable pharmaceutical lubricant (including calcium or magnesium soap) is added to the mixture of ingredients, preferably after which the mixture is compressed onto a shaped solid tablet core. A particularly preferred lubricant is sodium stearyl fumarate (National Drug Collection), sold by Penwest Pharmaceuticals under the trademark Pruv®.

In certain embodiments, the present invention further relates to a method of making a delayed release solid oral dosage form (eg, tablet) of the present invention. In certain preferred embodiments, the steps for preparing a delayed release oral solid dosage form of the present invention may include:
Preparation of inner core formulation:
1. (A) An active ingredient (for example, a drug) is granulated by a wet granulation method with an additive as necessary, and then dried and pulverized (if necessary) to obtain granules; or (B) an active ingredient is optionally used Dry-mix using the additive and, if necessary, geometric diluent to obtain granules;
2. If necessary, add additives in a suitable mix to the material prepared in step 1 for further granulation;
3. Preferably, the powder mixture prepared in step 1 or 2 is lubricated;
4). Using the powder mixture prepared in step 3 and compressing the core with a suitable compressor;
5. Apply a functional film coating on the tablet core prepared in step 4 if necessary;
The preparation of a delayed release (compression) coating may be performed, for example, as follows:
6). (A) Gum (eg, heteropolysaccharide gum and homopolysaccharide gum) is granulated by wet granulation with optional additives to produce a delayed release agent (agglomerated particles) and then the delayed release agent is dried; or (B) Dry mix the gum with optional additives to produce a delayed release agent (granules);
7). Preferably, the delayed release agent prepared in step 6 is milled;
8). Preferably, the delayed release agent prepared in step 6 or 7 is smoothed;
Inner core coating:
9. The delayed release agent prepared in Step 6-8 is compression coated onto the tablet core prepared in Step 1-5;
10. If necessary, the final dosage form is coated with a film (if desired).

  In one embodiment, for example, when using the Dry-Cota Press described below, steps 4 and 10 are combined into a single unit operation. Functional coating of tablet cores can be done using a Dry-Cota Press if the compressor is modified and equipped with a core tablet loading system.

  The Manesty Dry-Cota Press compressor consists of two side-by-side connected tablet presses, in which one press produces a core, which is then automatically moved to the next press for compression coating. Each “press” has an independent powder dosing mechanism whereby the core mixture is introduced into one machine and the coating mixture into the other. The automatic transfer arm rotates between the machines, removes the core from one press and moves them to the coating press. Other and more modern types of presses that may be used (eg Elizabeth Hata HT-AP 44-MSU-C, Killian RUD, Fette PT 4090) have a co-feed system of coating mixture and molded core . This shape is more flexible, and the core can be pan-coated with a cosmetic or cosmetic coating prior to compression coating. Furthermore, this makes it possible to apply a plurality of compression coating layers by circulating tablets that have already been compression coated. Both types of presses have a mechanism that centers the tablet within the coating both vertically and radically. As will be appreciated by those skilled in the art, other tablet presses may be used to provide the final dosage form of the present invention.

  In general, the compression coating surrounds the entire core, but in certain embodiments of the invention, the compression coating substantially surrounds the tablet core but does not completely surround it. In such a case, drug release from the tablet core occurs first from the uncompressed portion of the inner core. In other embodiments of the invention, the compression coating is not applied to the entire inner core at the same thickness, thus creating a portion of the compressed dosage form that releases the drug earlier (and slower) than the other portions. This may be done, for example, by applying a compression coating to the core so that it is not centered in the press.

  For best results, the tablets produced from the core compression coating are about 4 to about 25 kP, preferably about 5 to about 15 kP, and most preferably about 8 to about 9 kP in hardness. In certain preferred embodiments, the diameter may be up to 5/8 inches or more for circular compression coated tablets, and the diameter may be up to 3/4 inches or more for caplet type compression coated tablets. The average flow of (uncompressed) coatings prepared in accordance with the present invention is from about 25 to about 40 g / sec.

  In certain embodiments of the invention, the compression coated tablets may then be further coated with an enteric coating material or a hydrophobic material. Examples of suitable enteric polymers include cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trichloride. There are melittes and mixtures of any of the above. An example of a suitable commercially available enteric material is that available under the trade name Eudragit® L30D55.

  In further embodiments, the dosage form may be coated with a hydrophilic coating in addition to or instead of the enteric or hydrophobic coating described above. An example of a suitable material that may be used in these hydrophilic coatings is hydroxypropylmethylcellulose (eg, sold by Opadry®, Colorcon, West Point, Pennsylvania).

  In yet another embodiment, optional enteric and / or hydrophobic and / or hydrophilic coatings may be applied as an intermediate layer between the core and the compression coating, as an alternative or in addition.

  Optionally enteric and / or hydrophobic and / or hydrophilic coatings may be applied in a pharmaceutically acceptable manner well known to those skilled in the art. For example, in certain embodiments, the coating is applied through a fluidized bed or in a coating pan. For example, the coated tablets may be dried in a coating pan, for example at about 60-70 ° C. for about 3-4 hours. The solvent for the hydrophobic polymer or enteric coating may be an organic solvent, an aqueous solvent, or a mixture of organic and aqueous solvents. The organic solvent may be, for example, isopropyl alcohol, ethanol, etc. containing or not containing water.

  In a further embodiment of the invention, support platforms are applied to tablets made according to the invention. Suitable support platforms are well known to those skilled in the art. An example of a suitable support platform is described, for example, in US Pat. No. 4,839,177, which is hereby incorporated by reference. In this patent, the support platform consists of a polymeric material that partially coats the tablet and is insoluble in aqueous solution. The support platform may be designed to maintain its impermeability, for example, during the transfer of a therapeutically active pharmaceutical product. The support platform may be formed by spraying a polymer material containing the support platform over all or part of the tablet surface, for example, via a compression coating on a part of the tablet surface, or by immersing the tablet in a solution of the polymer material. It may be applied to tablets.

  The support platform may be, for example, about 2 mm thick when applied by compression and about 10 microns thick when applied by spray coating or dip coating. In general, in embodiments of the invention where a hydrophobic polymer or enteric coating is applied to the tablet over the delayed release coating, the tablet is weight increased from about 1 to about 20%, and in some preferred embodiments from about 5% to about 10%. Coat until

  Materials useful for the hydrophobic coating and support platform of the present invention include derivatives of acrylic acid (eg, acrylic acid, esters of methacrylic acid, and copolymers thereof), cellulose and its derivatives (eg, ethyl cellulose), polyvinyl alcohol, and the like.

  As noted above, the core and / or compression coating is a suitable amount of, for example, a lubricant, binder, granulation aid, diluent, colorant, flavoring agent, and leveling agent, conventional in the pharmaceutical arts. You may contain anything.

  Examples of binders suitable for use in the present invention include, but are not limited to, for example, povidone, polyvinylpyrrolidone, xanthan gum, cellulose gums such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxycellulose, gelatin, starch, and pregelatinized starch. There is.

  Examples of suitable leveling agents for use in the present invention include talc, silicon dioxide, and corn starch.

  In certain embodiments of the invention, the tablet core contains an additional dose of drug (or a therapeutically effective amount of another drug), which is contained in either a hydrophobic or enteric coating (as appropriate). Or an additional (optional) coating that covers the outer surface of the tablet core (without a hydrophobic or enteric coating), or a compression coating (and hydrophobic and, where applicable) And / or an enteric coating substance) as a further coating layer covering the surface of the base coating. This may be desirable, for example, when drug loading is required to provide a therapeutically effective blood level of the active substance when the formulation is first exposed to gastric juice. The loading amount of the drug contained in the coating layer may be, for example, from about 10% to about 40% of the total amount of the drug contained in the formulation.

Examples of agents suitable for introduction into the present invention include the following:
Antihistamines such as azatazine maleate, bromophenylamine maleate, carbinoxamine maleate, chlorphenylamine maleate, dexchlorphenylamine maleate, diphenhydramine hydrochloride, doxylamine succinate, methodirazine hydrochloride, promethazine, trimeprazine tartrate, tripelenamine tartrate, Tripelenamine hydrochloride and triprolidine hydrochloride);
Antibiotics (eg penicillin V potassium, cloxacillin sodium, dicloxacillin sodium, nafcillin sodium, oxacillin sodium, carbenicillin indanyl sodium, oxytetracycline hydrochloride, tetracycline hydrochloride, clindamycin phosphate, clindamycin hydrochloride, palmitic hydrochloride Clindamycin palmitate (CLdamycin palmitate HCL), lincomycin hydrochloride, novobiocin sodium, sodium nitrofurantoin, metronidazole hydrochloride); anti-antagonists (eg isoniazid);
Cholinergic agents (eg ambenonium chloride, betanechol chloride, neostigmine bromide, pyridostigmine bromide);
Antimuscarinic agents (eg methyl anisotropin bromide, clinidium bromide, dicyclomine hydrochloride, glycopyrrolate, hexocyclium methyl sulfate, methylformatropin bromide, hyoscyamine sulfate, methanethelin bromide, hyoscine hydrobromide, odor Oxyphenonium bromide, propanterin bromide, tridihexetyl chloride);
Sympathomimetic substances (eg, bitorterol mesylate, ephedrine, ephedrine hydrochloride, ephedrine sulfate, orciprenaline sulfate, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ritodrine hydrochloride, salbutamol sulfate, terbutaline sulfate);
Sympatholytic substances (eg phenoxybenzamine hydrochloride); other autonomic agents (eg nicotine);
Iron preparations (eg ferrous gluconate, ferrous sulfate);
Hemostatic agents (eg aminocaproic acid);
Cardiotonics (eg acebutol hydrochloride, disopyramide phosphate, flecainide acetate, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate, timolol maleate, tocainide hydrochloride, verapamil hydrochloride);
Antihypertensive agents (eg captopril, clonidine hydrochloride, hydralazine hydrochloride, mecamylamine hydrochloride, metoprolol tartrate); vasodilators (eg papaverine hydrochloride);
Non-steroidal anti-inflammatory agents (eg choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, meclofenamate sodium, naproxen sodium, tolmethine sodium);
Opiate agonists (e.g., codeine hydrochloride, codeine phosphate, codeine sulfate, dextromorphamide tartrate, hydrocodone tartrate, hydromorphone hydrochloride, pethidine hydrochloride, methadone hydrochloride, morphine sulfate, morphine acetate, morphine lactate, morphine meconate, morphine nitrate, Morphine monobasic phosphate, morphine tartrate, morphine valerate, morphine hydrobromide, morphine hydrochloride, propoxyphene hydrochloride);
Anticonvulsants (eg phenobarbital sodium, phenytoin sodium, troxidone, ethosuximide, valproate sodium);
Tranquilizers (eg acetophenazine maleate, chlorpromazine hydrochloride, fluphenazine hydrochloride, prochlorperazine edicylate, promethazine hydrochloride, thioridazine hydrochloride, trifluoroperazine hydrochloride, lithium citrate, molindone hydrochloride, thiothixine hydrochloride) ;
Chemotherapeutic drugs (eg doxorubicin, cisplatin, floxuridine, methotrexate, combinations thereof);
Lipid lowering agents (eg gemfibrozil, clofibrate, HMG-CoA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin, etc.);
H ₂ antagonists (eg, cimetidine, famotidine, nizatidine, ranitidine hydrochloride, etc.);
Anticoagulants and antiplatelet agents (eg, warfarin, cipyridamole, ticlopidine, etc.);
Bronchodilators (eg albuterol, isopreterenol, metaproterenol, terbutaline, etc.);
Stimulants (eg benzamphetamine hydrochloride, dexamphetamine sulfate, dexamphetamine phosphate, diethylpropion hydrochloride, fenfluramine hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, phendimetrazine tartrate, phenmetrazine hydrochloride , Caffeine citrate);
Barbiturates (eg, amylobarbital sodium, butabarbital sodium, secobarbital sodium);
Sedatives (eg, hydroxyzine hydrochloride, mesprilon); expectorants (eg, potassium iodide);
Antiemetics (for example, benzaquinamide hydrochloride, metoclopropamide hydrochloride, trimethobenzamide hydrochloride);
Gastrointestinal agents (eg ranitidine hydrochloride); heavy metal antagonists (eg penicillamine, penicillamine hydrochloride);
An antithyroid agent (eg, methimazole);
Genitourinary smooth muscle relaxants (eg flavoxate hydrochloride, oxybutynin hydrochloride);
Vitamins (eg thiamine hydrochloride, ascorbic acid);
Unclassified drugs (eg amantadine hydrochloride, colchicine, etidronate disodium, leucovorin calcium, methylene blue, potassium chloride, pralidoxime chloride.

  Steroids, especially glucocorticoids (eg prednisolone, prednisone, cortisone, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, triamcinolone).

  The drugs may be used in their base for or a pharmaceutically acceptable salt or complex may be used. The above list of possible therapeutic agents or specific agents is merely illustrative and is not intended to limit the scope of the invention in any way.

  The chronotherapy formulations of the present invention may be used to treat conditions known to (or become known to) those skilled in the art that such treatment is beneficial. These treatments include, but are not limited to, allergic rhinitis, attention deficit disorder, asthma, arthritis, cancer treatment, cardiovascular disorders, high cholesterol, hypertension, and ulcers.

  With regard to allergic rhinitis, the main symptoms, sneezing, runny nose and stuffy nose are generally worse at waking than during active hours on a given day. The chronotherapy of the present invention also promotes eye recovery resulting from sneezing, nasal congestion, runny nose, and allergies. For example, hay fever symptoms peak in the morning. Several studies have shown that taking antihistamines in the evening instead of during the day suppresses symptoms before the patient wakes up, rather than waiting for the onset of symptoms. Thus, a time-treatment oral formulation (such as an antihistamine) that is taken at a convenient time and releases the dose at some point, thereby maximizing the effect of the dosage form in the morning It is highly desirable to provide.

  With respect to asthma, normal lung function changes in a 24-hour cycle and becomes low early in the morning. This decrease (dip) is specifically called asthma. Time treatment for asthma aims at obtaining maximum effect from bronchodilators in the early morning. The key to managing asthma cases is chronotherapy, and it has been proposed that treatment to improve nighttime asthma can improve signs of asthma during the day (proferred). Indeed, dosage and timing have been linked for asthmatic patients, and the number of those patients has doubled in the United States alone since 1975. Most asthmatics get worse most at night, probably because the body's natural anti-inflammatory agent, cortisol, is at its lowest level. Since the most common seizure time is 4 am, in many cases the pain of asthma itself is exacerbated by the additional pain of insomnia. Thus, when taken at a convenient time, it releases the dose, for example shortly before 4 am, so that the effect of the dosage form is maximized at that time (for example, antihistamines ) It would be highly desirable to provide a time treatment oral formulation.

  The chronotherapy formulation of the present invention may be used to treat arthritis. Glucocorticoids have a very favorable effect on the symptoms of rheumatoid arthritis, such as morning stiffness, joint pain, and joint swelling. For arthritis, a temporal biological pattern has been observed in joint pain. People with osteoarthritis (the most common type of arthritis) tend to have less pain in the morning and stronger at night. However, in people with rheumatoid arthritis, pain usually peaks in the morning and decreases over the course of the day. Recent animal experiments show that arthritis in rats fluctuates over 24 hours and supports these observations by both patients and physicians. Possible drug candidates in this therapeutic area include standard treatments (for all types of arthritis), NSAIDs and corticosteroids. Preferably, the time of administration should be set to ensure that the time when the blood level of the drug is highest is coincident with the peak of pain. In osteoarthritis, the optimal time for NSAIDs (such as ibuprofen) is approximately noon or mid-afternoon. In rheumatoid arthritis, the best time to take NSAIDs is after dinner.

  For attention deficit disorder, it has been observed that sustained-release formulations have lower peak plasma concentrations of drugs, and in some cases, sustained release of methylphenidate is less effective than conventional dosage forms Has been observed. A dosage form that delays the release of the most effective amount of drug to treat attention deficit disorder, particularly where the active substance is first released in a single dose, followed by a predictable delay, followed by an active It is useful if a second release of the substance occurs. Possible drug candidates include stimulants such as methylphenidate and pharmaceutically acceptable salts thereof.

  With regard to cancer treatment, animal studies have suggested that time treatment can be more effective and less toxic if cancer therapeutics are administered at carefully selected times. Currently, studies suggest that there may be different temporal biological cycles between normal and tumor cells. If this is true, the goal is to align the time of cancer therapeutic administration with the temporal biological cycle of the tumor cells, making it more effective against cancer and less toxic to normal tissues. Possible drug candidates include, for example, injection solutions such as doxorubicin and cisplatin (in combination), and floxuridine.

  In the treatment of cardiovascular disorders, chronotherapy is not entirely new. Since 1986, patients suffering from angina have been treated with nitroglycerin patches, which are applied to the chest or shoulders of patients in the morning and removed in the evening. This is not “side door” because it is not based on the recognition that the disease should be treated at that time of the day to worsen at that time of the day. Considered time treatment. Rather this comes from the recognition that nitroglycerin is not effective when administered continuously. Based on the fact that there is a 24-hour pattern in heart disease, the use of the chronotherapy formulation of the present invention is highly preferred. Those skilled in the art have recognized that heart attacks, sudden death, angina, and stroke are all most common in the morning. Accordingly, it would be highly desirable to provide a time-treated oral formulation that is taken at a convenient time and the dose is released so that the effect of the dosage form is maximized at that time. Possible drug candidates include antihypertensive agents, anti-ischemic agents, and agents that control blood coagulation.

  With respect to hypertension, blood pressure fluctuates over 24 hours (daily). In most normotensive patients and most essential hypertensive patients (systemic vasoconstriction is associated with increased peripheral vascular tolerance in arterioles), circadian mechanisms and activity and stress during sleep / activity cycles Due to the difference, the blood pressure suddenly rises when getting up. After peaking during daytime activity, blood pressure falls from 10% to 20% of the average daytime level during sleep. Both blood pressure and heart rate generally rise early in the morning and myocardial oxygen demand increases significantly, which causes myocardial ischemia in patients with known or undiagnosed coronary artery disease. The sudden rise in blood pressure at waking is associated with a high incidence of morning cerebrovascular stroke and myocardial infarction. In addition, cerebrovascular stroke and other cardiovascular events (sudden death, acute myocardial infarction, and all ischemic burden) are circadian and have the first 6 hours of activity (from 6 am) It is observed from the results of the Framingham study that it is most common during noon) and least during sleep. Theoretically, increased blood pressure in the morning destroys coronary atherosclerotic plaque, potentially damaged tissue, and promotes clot formation early in the morning when the clotting process is most active. Accordingly, it is highly desirable to provide a time-treated oral formulation that is taken at a convenient time and releases the dose so that the effect of the dosage form is maximized at that time.

  In addition to a sudden rise in blood pressure when waking up, a “dip” in blood pressure occurs in most people during nighttime sleep. This dip may vary or may not be seen in more severe forms of hypertensive and secondary hypertensive patients, in which blood pressure does not drop as expected or during sleep Increases compared to daytime levels. Blood pressure patterns fall into four categories: (i) “dippers” show a 10% to 20% decrease in blood pressure during night sleep compared to the average blood pressure level during the day; ) “Nondippers” change nighttime blood pressure only slightly from daytime levels; (iii) “Superdippers” mean nighttime blood pressures are more than 20% above average daytime levels And (iv) “risers” have higher nighttime blood pressure compared to daytime levels. Deviations from normal circadian rhythm of blood pressure are associated with end organ damage and an increased risk of undesirable cardiovascular events. Hypertensive patients with nocturnal blood pressure patterns at night are more prone to eye, kidney, and heart abnormalities and have a higher rate of cardiovascular events such as cerebrovascular stroke and myocardial infarction than normal dipper.

  Chronic treatment is a treatment that allows for better control of daytime and nighttime blood pressure by delivering an amount of the drug proportional to the patient's needs and thereby synchronizing with the circadian rhythm of blood pressure. Is the law. Deliver more time-treated antihypertensive drugs in the morning and daytime when blood pressure is highest and generally deliver fewer drugs at night when blood pressure drops to the lowest level. Suppressing the rise in early morning blood pressure and heart rate by using a suitable delivery system to administer the required medication over time can theoretically reduce the incidence of early morning cardiovascular events. .

  Verapamil, a calcium channel blocker, lowers heart rate and blood pressure and is particularly useful for patients suffering from both ischemic heart disease and hypertension. Due to these properties of verapamil and its half-life, verapamil is a good choice as an anti-hypertensive formulation with a chronotherapeutic oral drug absorption system (CODAS). This system is designed to be taken at bedtime, with an initial delay in drug delivery of 4 to 5 hours, after which the drug is controlled release. CODAS-verapamil capsules (Verelan® PM) were produced using CODAS multiparticulate technology with beads coated with verapamil. When taken as directed, the formulation has the highest verapamil concentration in plasma around the morning when waking up. Studies have shown that administration of verapamil chronotherapy at night can better control rapid blood pressure increases in the morning than conventional antihypertensive agents. Verapamil remedies are also administered at bedtime to control daytime blood pressure without excessively lowering hypotension or nighttime blood pressure, reducing the risk of target organ damage due to insufficient perfusion pressure To do. Furthermore, verapamil chronotherapy drugs are designed to carry more pharmaceuticals during the day than conventional verapamil and other antihypertensive agents. Possible drug candidates include antihypertensive agents such as calcium channel blockers.

  Pharmaceuticals for controlling high cholesterol, such as HMG-CoA reductase inhibitors, are also expected to work better when administered in the evening when enzyme activity levels peak. Accordingly, it is highly desirable to provide a time-treated oral formulation that is taken at a convenient time and releases the dose so that the effect of the dosage form is maximized at that time.

  Treatment of ulcers is another example where timing is important. Since it is known that the acidity produced from the stomach peaks at 6 pm, pharmaceuticals that reduce acid secretion in the stomach can be delivered accordingly.

  An advantage of chronotherapy is that it is a safer and more effective treatment than conventional therapies. This is due to the more drugs being delivered the greater the risk of illness, and the less likely the disease symptoms are. Another advantage of the present invention is that it has a high quality of life and is a once-daily drug delivery system that increases patient compliance.

  In certain preferred embodiments of the invention where the symptoms of the disease state to be treated (eg, asthma attack, arthritic pain) are greatest upon waking, the time treatment formulation is preferably at bedtime (eg, approximately 9 or 10 pm). ) With a lag time of about 5 or 6 hours, so that a substantial portion of the drug, for example in a compression-coated delayed release oral dosage form, is for example between 2-3 am or 3 am Released during -4 hours, the drug is absorbed from the gastrointestinal tract and provides therapeutic efficacy at a time correlated to the peak of the symptoms of the disease state.

  When the active agent is a low dose active agent (eg, an agent administered at a (unit) dose of about 0.01 mg to about 40 mg), in certain preferred embodiments, the total weight of the tablet is from about 220 mg to about 900 mg. The weight of the core is preferably from about 50 mg to about 170 mg. Preferably the core is about 5 to about 23 weight percent, most preferably about 18 to about 20 weight percent of the total weight of the tablet. In embodiments where the active agent is a low dose active agent, the coating is preferably from about 150 mg to about 850 mg. Preferably, the coating is about 75 to about 94 weight percent, and most preferably about 78 to 80 weight percent of the total weight of the tablet. Preferably, when the active agent is a low dose active agent, the ratio of core to gum (in the compression coating) is from about 1: 0.37 to about 1: 5, preferably from about 1: 0.37 to about 1. : 1.12, most preferably about 1: 0.75. When the active agent is a low dose active agent, the ratio of core to compression coating material (all ingredients) is preferably from about 1: 2 to about 1: 9, and in some preferred embodiments more preferably about 1: 4. It is.

  When the active agent is a relatively high dose active agent (eg, an agent administered at a (unit) dose of about 41 mg to about 300 mg), the ratio of core to gum (in the compression coating) is about 1: 0. .3 to about 1: 3, preferably about 1: 0.6 to about 1: 1.5. In certain embodiments, preferably when the active agent is a high dose active agent, the ratio of core to compression coating material (all ingredients) is from about 1: 1 to about 1: 5, preferably from about 1: 2 to about 1: 3. When the active agent is a relatively high dose of active agent, the total weight of the tablet is preferably from about 500 mg to about 1500 mg, more preferably from about 750 mg to about 1000 mg. About 1: 9, and in some preferred embodiments more preferably about 1: 4.

  In the accompanying examples, the core containing the active ingredient is generally compression coated with the coating formulation manually by a rotary tablet press. In those processes, approximately half of the outer core material is first added to the mold. Generally, the inner core tablet is centered on the powder bed and coated with the other half of the outer coating powder. However, as will be appreciated by those skilled in the art, the compression coating may be performed by an automated tablet press for commercialization. Prior to compression coating in a tablet press, preferably 0.75% Pruv® (sodium stearyl fumarate (US National Pharmaceuticals)) or other suitable lubricant is added to the compression coating material. In certain embodiments where the coating requires gum, for example, if it is 50% xanthan gum (XG), the coating contains 50% xanthan gum diluted with dextrose; for example, if it is 50% locust bean gum (LBG), the coating is dextrose. Contains 50% locust bean gum diluted with

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. They should not be construed as limiting the scope of the claims in any way.

工程：
１．必要量のキサンタンガム、ローカストビーンガム、およびデキストロースを高速混合機／造粒機で３分間乾式混合する。 Example 1
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 1 below:

Process:
1. The required amounts of xanthan gum, locust bean gum, and dextrose are dry mixed in a high speed mixer / granulator for 3 minutes.

2. Water (125-150 ml) is added to the dry mixture and granulated for an additional 3 minutes.

3. The granules are then dried in a fluid bed dryer to an LOD (loss on drying) of less than about 10% by weight (eg, 4-7% LOD).

工程：
１．必要量のキサンタンガム、ローカストビーンガム、硫酸カルシウム、およびデキストロースを高速混合機／造粒機で３分間乾式混合する。 (Example 2)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 2 below:

Process:
1. The required amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose are dry mixed in a high speed mixer / granulator for 3 minutes.

2. Ethyl cellulose is dissolved in ethyl alcohol to prepare a slurry of a hydrophobic polymer (ethyl cellulose).

3. Add the slurry to the dry mix and granulate for an additional 3 minutes.

4). The granules are then dried in a fluid bed dryer to an LOD (loss on drying) of less than about 10% by weight (eg, 4-7% LOD).

工程：
１．必要量のキサンタンガム、ローカストビーンガム、硫酸カルシウム、およびデキストロースを高速混合機／造粒機で３分間乾式混合する。 (Example 3)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 3 below:

Process:
1. The required amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose are dry mixed in a high speed mixer / granulator for 3 minutes.

2. Water (125-150 ml) is added to the dry mixture and granulated for an additional 3 minutes.

3. The granules are then dried in a fluid bed dryer to an LOD (loss on drying) of less than about 10% by weight (eg, 4-7% LOD).

工程：
実施例１と同じ工程を使用して実施例４の遅延放出コーティングを調製する。 Example 4
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 4 below:

Process:
The delayed release coating of Example 4 is prepared using the same process as Example 1.

工程：
実施例３と同じ工程を使用して実施例５における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 5)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 5 below:

Process:
The same process as in Example 3 is used to prepare the delayed release agent used in the inventive compression coating in Example 5.

工程：
実施例３と同じ工程を使用して実施例６における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 6)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 6 below:

Process:
The same process as in Example 3 is used to prepare the delayed release agent used in the inventive compression coating in Example 6.

工程：
実施例１と同じ工程を使用して実施例７における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 7)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 7 below:

Process:
The same process as in Example 1 is used to prepare the delayed release agent used in the inventive compression coating in Example 7.

工程：
実施例１と同じ工程を使用して実施例８における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 8)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 8 below:

Process:
The same process as in Example 1 is used to prepare the delayed release agent used in the inventive compression coating in Example 8.

工程：
実施例１と同じ工程を使用し、デキストロースの代わりにラクトースを使用して、実施例５における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 Example 9
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 9 below:

Process:
The delayed release agent used in the inventive compression coating in Example 5 is prepared using the same process as in Example 1 but using lactose instead of dextrose.

工程：
１．必要量のキサンタンガム、ローカストビーンガム、マンニトール、およびヒドロキシプロピルメチルセルロースを高速混合機／造粒機で３分間乾式混合する。 (Example 10)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 10 below:

Process:
1. The required amount of xanthan gum, locust bean gum, mannitol, and hydroxypropyl methylcellulose are dry mixed in a high speed mixer / granulator for 3 minutes.

2. Water (125-150 ml) is added to the dry mixture and granulated for an additional 3 minutes.

3. The granules are then dried in a fluid bed dryer to an LOD (loss on drying) of less than about 10% by weight (eg, 4-7% LOD).

工程：
実施例１と同じ工程を使用し、デキストロースの代わりにマンニトールを使用して、実施例１１における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 11)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 11 below:

Process:
Prepare the delayed release agent used in the compression coating of the invention in Example 11 using the same process as in Example 1 but using mannitol instead of dextrose.

工程：
実施例１０と同じ工程を使用して、実施例１２における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 12)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 12 below:

Process:
The same process as in Example 10 is used to prepare the delayed release agent used in the inventive compression coating in Example 12.

工程：
実施例１２と同じ工程を使用して、実施例１３における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 13)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 13 below:

Process:
The same process as Example 12 is used to prepare the delayed release agent used in the inventive compression coating in Example 13.

工程：
実施例１２と同じ工程を使用して、実施例１４における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 14)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 14 below:

Process:
The same process as in Example 12 is used to prepare the delayed release agent used in the inventive compression coating in Example 14.

工程：
実施例１２と同じ工程を使用して、実施例１５における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 15)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 15 below:

Process:
The same process as Example 12 is used to prepare the delayed release agent used in the inventive compression coating in Example 15.

工程：
実施例１２と同じ工程を使用して、実施例１６における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 16)
A delayed release coating is prepared with the formulation described in Table 16 below:

Process:
The same process as in Example 12 is used to prepare the delayed release agent used in the inventive compression coating in Example 16.

工程：
１．必要量のキサンタンガム、ローカストビーンガム、デキストロース、および微結晶セルロースを高速混合機／造粒機で３分間乾式混合する。 (Example 17)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 17 below:

Process:
1. The required amounts of xanthan gum, locust bean gum, dextrose, and microcrystalline cellulose are dry mixed in a high speed mixer / granulator for 3 minutes.

2. Water (125-150 ml) is added to the dry mixture and granulated for an additional 3 minutes.

3. The granules are then dried in a fluid bed dryer to an LOD (loss on drying) of less than about 10% by weight (eg, 4-7% LOD).

工程：
実施例１と同じ工程を使用し、デキストロースの代わりに微結晶セルロースを使用して、実施例１８における本発明の圧縮コーティングに使用される遅延放出剤を調製する。 (Example 18)
The delayed release agent used in the compression coating of the present invention is prepared with the formulation described in Table 18 below:

Process:
The delayed release agent used in the inventive compression coating in Example 18 is prepared using the same process as in Example 1 but using microcrystalline cellulose instead of dextrose.

工程：
１．必要量のプレドニゾロンおよびProsolv（商標） SMCC 50をV-混合機を使用して５分から１０分間混合する。 (Example 19)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 19:

Process:
1. Mix the required amount of prednisolone and Prosolv ™ SMCC 50 for 5-10 minutes using a V-mixer.

2. Add the required amount of Prosolv ™ SMCC 90, Explotab ™, and sodium carboxymethylcellulose to the mixture and continue mixing for an additional 5 minutes.

3. Add the required amount of Pruv to the mixture and mix for an additional 5 minutes.

4). Compress the tablet core using a tablet press.

工程：
１．必要量のプレドニゾロン、Prosolv（商標） SMCC 90、Explotab（登録商標）を５分から１０分間混合する。 (Example 20)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 20:

Process:
1. The required amount of prednisolone, Prosolv ™ SMCC 90, Explotab ™ is mixed for 5 to 10 minutes.

2. Add the required amount of Pruv and PVP to the mixture and mix for an additional 5 minutes.

3. Compress the tablet core using a tablet press.

工程：
１．必要量のプレドニゾロン、Prosolv（商標） SMCC 90、Explotab（登録商標）、およびカルボキシメチルセルロースナトリウムを５分から１０分間混合する。 (Example 21)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 21:

Process:
1. Mix the required amount of prednisolone, Prosolv ™ SMCC 90, Explotab ™, and sodium carboxymethylcellulose for 5 to 10 minutes.

2. Add the required amount of Pruv and PVP to the mixture and mix for an additional 5 minutes.

3. Compress the tablet core using a tablet press.

工程：
１．必要量のプレドニゾロンおよびProsolv（商標） SMCC 50をV-混合機を使用して５分から１０分間混合する。 (Example 22)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 22:

Process:
1. Mix the required amount of prednisolone and Prosolv ™ SMCC 50 for 5-10 minutes using a V-mixer.

2. Add the required amount of Prosolv ™ SMCC 90, Explotab ™, PVP, and talc to the mixture and continue mixing for another 5 minutes.

3. Add the required amount of Pruv to the mixture and mix for an additional 5 minutes.

4). Compress the tablet core using a tablet press.

工程：
１．必要量のプレドニゾロンおよびProsolv（商標） SMCC 50をV-混合機を使用して５分から１０分間混合する。 (Example 23)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 23:

Process:
1. Mix the required amount of prednisolone and Prosolv ™ SMCC 50 for 5-10 minutes using a V-mixer.

2. The required amount of Prosolv ™ SMCC 90, Explotab®, sodium carboxymethylcellulose, and talc are added to the mixture and mixing is continued for another 5 minutes.

3. Add the required amount of Pruv to the mixture and mix for an additional 5 minutes.

4). Compress the tablet core using a tablet press.

工程：
実施例２３と同じ工程を使用して実施例２４のコアを調製する。 (Example 24)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 24:

Process:
The core of Example 24 is prepared using the same process as Example 23.

工程：
実施例２３と同じ工程を使用し、Explotab（登録商標）およびカルボキシメチルセルロースナトリウムを含有させずに、実施例２５のコアを調製する。 (Example 25)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 25:

Process:
The core of Example 25 is prepared using the same process as Example 23 but without Explotab® and sodium carboxymethylcellulose.

工程：
実施例２３と同じ工程を使用し、カルボキシメチルセルロースナトリウムを含有させずに、実施例２６のコアを調製する。 (Example 26)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 26:

Process:
The core of Example 26 is prepared using the same process as Example 23, but without sodium carboxymethylcellulose.

工程：
実施例２３と同じ工程を使用して実施例２７のコアを調製する。 (Example 27)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 27:

Process:
The core of Example 27 is prepared using the same process as Example 23.

工程：
実施例２３と同じ工程を使用し、Explotab（登録商標）を含有させずに、実施例２８のコアを調製する。 (Example 28)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 28:

Process:
The core of Example 28 is prepared using the same process as Example 23, but without the Explotab®.

工程：
実施例２３と同じ工程を使用して実施例２９のコアを調製する。 (Example 29)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 29:

Process:
The core of Example 29 is prepared using the same process as Example 23.

工程：
実施例２３と同じ工程を使用し、Explotab（登録商標）を含有させずに、実施例３０のコアを調製する。 (Example 30)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 30:

Process:
The core of Example 30 is prepared using the same process as Example 23, but containing no Explotab®.

工程：
実施例２３と同じ工程を使用し、カルボキシメチルセルロースナトリウムを含有させずに、実施例３１のコアを調製する。 (Example 31)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 31:

Process:
The core of Example 31 is prepared using the same process as Example 23 but without sodium carboxymethylcellulose.

工程：
実施例２３と同じ工程を使用し、カルボキシメチルセルロースナトリウムを含有させずに、実施例３２のコアを調製する。 (Example 32)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 32:

Process:
The core of Example 32 is prepared using the same process as Example 23 but without sodium carboxymethylcellulose.

工程：
実施例２３と同じ工程を使用し、カルボキシメチルセルロースナトリウムを含有させずに、実施例３３のコアを調製する。 (Example 33)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 33:

Process:
The core of Example 33 is prepared using the same process as Example 23, but without sodium carboxymethylcellulose.

工程：
実施例２３と同じ工程を使用して実施例３４のコアを調製する。 (Example 34)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 34:

Process:
The core of Example 34 is prepared using the same process as Example 23.

工程：
実施例２３と同じ工程を使用し、Explotab（登録商標）を含有させずに、実施例３５のコアを調製する。 (Example 35)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 35:

Process:
The core of Example 35 is prepared using the same process as Example 23, but without Explotab®.

工程：
実施例２３と同じ工程を使用して実施例３６のコアを調製する。 (Example 36)
A prednisolone core composition is prepared with the formulation ingredients listed in Table 36:

Process:
The core of Example 36 is prepared using the same process as Example 23.

工程：
１．必要量の即時放出コアを秤量し、置いておく。 (Examples 37-39)
In Examples 37-39, prednisolone tablets having the core formulation described in Example 21 and the coating formulation described in Example 3 were prepared. The tablet formulations for Examples 37-39 are listed in Table 37 below.

Process:
1. Weigh and place the required amount of immediate release core.

2. Mix 0.75 wt% Pruv (R) sodium stearyl fumarate (National Medicines Collection), sold by Edward Mendell, with the required amount of coating for 5 minutes.

3. Weigh approximately half of the compression coating.

4). The lower layer of compression coating is poured into the lower punch of the mold.

5. Place an immediate release core in the center of the compression coating.

6). The upper layer is poured into the mold.

7). Rotate and compress the punch station.

8). Weigh the finished tablet to make sure it is the right weight.

実施例３７-３９の錠剤の結果は表３９に記載するように以下の遅延時間（錠剤からプレドニゾロンが放出される時間）および完全放出時間（錠剤から全てのプレドニゾロンが放出される時間）であった：

（実施例４０-４２）
実施例４０-４２では、実施例２１に記載するコア製剤および実施例２に記載するコーティング製剤を有するプレドニゾロン錠剤を調製した。実施例４０-４２の錠剤処方を以下の表４０に記載する。

工程：
実施例３７-３９と同じ工程を使用して実施例４０-４２の錠剤を調製する。 The tablets of Examples 37-39 were tested at 15 dip / min (dpm) using 250 mL of deionized water using US Pharmacopoeia type III, with the results shown in Table 38 below:

The results of the tablets of Examples 37-39 were as follows in Table 39 with the following delay times (time when prednisolone was released from the tablet) and complete release time (time when all prednisolone was released from the tablet) :

(Examples 40-42)
In Examples 40-42, prednisolone tablets having the core formulation described in Example 21 and the coating formulation described in Example 2 were prepared. The tablet formulations for Examples 40-42 are set forth in Table 40 below.

Process:
The tablets of Examples 40-42 are prepared using the same process as Examples 37-39.

実施例４０-４２の錠剤の結果は表４２に記載するように以下の遅延時間（錠剤からプレドニゾロンが放出される時間）および完全放出時間（錠剤から全てのプレドニゾロンが放出される時間）であった：

ここに見られるように、錠剤の総重量が（コーティング重量の増加によって）増加するほど、遅延時間および相当する放出時間が増加する傾向がある。 The tablets of Examples 40-42 were tested at 15 dip / min (dpm) using 250 mL of deionized water using US Pharmacopoeia type III, with the results shown in Table 41 below:

The results for the tablets of Examples 40-42 were the following lag time (time when prednisolone was released from the tablet) and complete release time (time when all prednisolone was released from the tablet) as described in Table 42 :

As can be seen, there is a tendency for the lag time and the corresponding release time to increase as the total weight of the tablet increases (by increasing the coating weight).

(Example 43)
In Example 43, various delayed release coating formulations were prepared to confirm the effect of the percentage of gum in the coating formulation on the release time and release rate of the active agent in the tablet core.

遅延放出圧縮コーティング中のガムの種々のパーセンテージの影響を以下の表に示す：

表４３ｂに示すように、２０％のガムを含有する製剤は３０％または５０％のガムを含有する製剤より速く活性物質を放出した。結果は、顆粒化した遅延放出の実施例ではガムの％のランク順位に従った。キサンタンガム（未顆粒化）はこの実施例における他の遅延放出コーティング（顆粒化ガムを含有）と同様にはならなかった（例えば同じ遅延放出を起こさなかった）。 The components of the various delayed release coated granules of this example having various gum percentages are as follows:

The effect of various percentages of gum in the delayed release compression coating is shown in the following table:

As shown in Table 43b, formulations containing 20% gum released the active substance faster than formulations containing 30% or 50% gum. The results followed the rank order of gum in the granulated delayed release examples. Xanthan gum (ungranulated) did not become similar to other delayed release coatings (containing granulated gum) in this example (eg, did not cause the same delayed release).

  As can be seen in the above results, the greater the amount of gum for the drug in the formulation, the corresponding increase in the lag time before drug release is observed.

(Example 44)
In Example 44, various examples of delayed release compression coating formulations were prepared and the effect of the ratio of drug in the tablet to gum in the coating formulation on the release time and release rate of the active agent in the tablet core was determined.

この実施例では、実施例８のコーティング（薬剤：ガムの比率が１：３３．７５）のガムは実施例３のコーティング製剤（薬剤：ガムの比率が１：５０．６）および実施例２のコーティング（薬剤：ガムの比率が１：８４．４）のいずれよりも速い放出時間を示した。キサンタンガムはそのものに関してはランク順位に従ったが（例えばより多くのガム総量を含有するより大きな錠剤はより長い遅延を示す）、顆粒化物質（実施例８、２、および３のコーティング）に関しては従わなかった。薬剤に対してガムの量が増加するほど、それに対応して遅延時間の増加が観察される。達した結論によれば、薬剤に対するガムの比率が増加するほど、薬剤の放出前の放出遅延時間が増加（延長）される。 The components of various delayed release coated granules are shown in the examples above. The effects of the various drug to gum ratios are listed in the table below.

In this example, the gum of Example 8 coating (drug: gum ratio 1: 33.75) is the same as the coating formulation of Example 3 (drug: gum ratio 1: 50.6) and of Example 2. It showed a faster release time than any of the coatings (drug: gum ratio 1: 84.4). Xanthan gum follows the rank order for itself (eg larger tablets containing more gum total show a longer delay), but for granulated material (coating of Examples 8, 2, and 3). There wasn't. As the amount of gum relative to the drug increases, a corresponding increase in lag time is observed. According to the conclusion reached, the greater the ratio of gum to drug, the greater (extended) the delayed release time before drug release.

(Example 45)
In Example 45, various lots of delayed release coating formulations were prepared to determine the effect of sustained release coating thickness on the release time and release rate of the active agent in the tablet core.

この実施例で、実施例８のコーティングを１７０ｍｇ含有する錠剤は実施例８のコーティングを２５０ｍｇ含有する錠剤より放出が速いことが観察された。従って、錠剤においてコーティングの厚さが増加するほどそれに対応して遅延時間の増加が観察される。達した結論によれば、コーティングが厚い錠剤ほど薬剤の放出前の遅延時間が長い。 The components of various inner core formulations are shown in the above examples, and the components of various delayed release coated granules are shown in Table 45. The effect of delayed release coating thickness is shown in the table below.

In this example, it was observed that tablets containing 170 mg of the coating of Example 8 released faster than tablets containing 250 mg of the coating of Example 8. Accordingly, a corresponding increase in delay time is observed as the coating thickness increases in the tablet. According to the conclusion reached, tablets with thicker coatings have longer delay times before drug release.

(Example 46)
In Example 46, the effect of adding additional granule additives to the delayed release coating of Example 2 was measured. In this example, the types of additives added were microcrystalline cellulose, polyvinyl pyrrolidone, and polyethylene glycol, and these additives were added at levels of 0, 5%, and 10%.

持続放出コーティングへの更なる顆粒添加剤の添加の影響を以下の表に示す。

この実施例において、５％および１０％のポリエチレングリコール6000を添加すると活性物質の放出がわずかに速まることが観察された。５％ PVP K-30を含有する錠剤も、対照に比較してわずかに短い遅延時間を示している。１０％ PVP K-30を含有する錠剤の放出速度および遅延時間は変化しなかった。１０％ MCCで調製した錠剤は遅延時間については変化を示さなかったが、５％ MCCではより遅かった。達した結論によれば、遅延時間は持続放出コーティング中への更なる添加剤の添加によって変化しうる。 The components of the inner core formulation of this example are shown in Example 24 above, and the components of the various delayed release coated granules of this example are shown in Example 2 above. The amount or percentage of additional granule additive added is listed in Tables 46a and 46b below:

The effect of adding additional granule additives to the sustained release coating is shown in the table below.

In this example, it was observed that the addition of 5% and 10% polyethylene glycol 6000 resulted in a slightly faster release of the active substance. Tablets containing 5% PVP K-30 also show a slightly shorter lag time compared to the control. The release rate and lag time of the tablets containing 10% PVP K-30 did not change. Tablets prepared with 10% MCC showed no change in lag time, but were slower with 5% MCC. According to the conclusion reached, the lag time can be altered by the addition of further additives in the sustained release coating.

(Example 47)
In Example 47, production of scaled-up sustained release coatings was performed to see if tablets produced on the production scale show a release profile similar to that of tablets produced on the experimental scale.

  In this example, tablets coated with a core were produced on an Elizabeth Hata production press. Tablets were compressed using a HT-AP44MSU-C44 station core coating press. The inner core of the tablet was a 1/4 inch flat round beveled edge with 170 mg and 8-10 kP tablets. The final tablets were 9 mm round-concave and were 525 and 560 mg, 8-10 kP tablets.

The production scale mixture had the following composition:
Internal core:
2% Prednisolone 40% Prosolv SMCC 50
47.75% Prosolv SMCC 90
6% croscarmellose sodium 2% starch glycol ester sodium 2% talc 0.25% sodium stearyl fumarate outer coating mixture:
Example 2 (containing 0.75% sodium stearyl fumarate)
For tablet production, the press speed was 9 to 12 rpm.

この実施例では、生産スケールで生産された錠剤は実験スケールで生成された錠剤と同様の放出プロフィ-ルを示すことが観察された。従って、達した結論によれば、調製および生成技術は問題なくスケールアップできる。 The impact of scaled-up production of delayed release coating is shown in the data points listed in Table 47 below.

In this example, it was observed that the tablets produced on the production scale show a release profile similar to the tablets produced on the experimental scale. Thus, according to the conclusions reached, the preparation and production techniques can be scaled up without problems.

実施例４８-５７の錠剤を、米国薬局方溶解器具III型を使用し、２５０ｍＬの水を用いて１５回浸漬／分 (ｄｐｍ) で試験し、以下の表５０に記載する結果を得た：

結果は、コア中に崩壊剤が含有されることにより活性物質がより迅速に製剤から放出されることを示した。 (Examples 48-57)
In Examples 48-57, prednisolone tablets were prepared to include a core formulation containing various amounts of disintegrant and the coating formulation described in Example 10. Each tablet had the same core weight, the same coating weight, and the same total tablet weight. The tablet formulations of Examples 48-57 are described in Tables 48 and 49 below:

The tablets of Examples 48-57 were tested at 15 dip / min (dpm) using 250 mL of water using United States Pharmacopeia Dissolving Instrument Type III, with the results listed in Table 50 below:

The results showed that the active substance was released from the formulation more rapidly by including a disintegrant in the core.

実施例５８-６０に記載する製剤を含有する錠剤を、米国薬局方器具III型を使用し、２５０ｍＬの水を用いて１５回浸漬／分 の溶解試験を行った。結果を以下の表５２に示す。

（実施例６１）
実施例６１では、実施例５９に記載する製剤を含有するプレドニゾロン錠剤を、ｐＨ、イオン強度、および浸漬速度に関して溶解の変化を試験した。評価したｐＨは１．５、７．５、およびｐＨ変化であった。 (Examples 58-60)
Examples 58-60 contain the core formulation of Example 24 and a coating formulation that combines Examples 2, 4 and Examples 2 and 4 (52% for Example 2 and 75% for Example 4). Prednisolone tablets were prepared as follows. Each tablet had the same core weight, the same coating weight, and the same total tablet weight. The tablet formulations of Examples 58-60 are set forth in Table 51 below:

Tablets containing the formulations described in Examples 58-60 were subjected to 15 dip / min dissolution tests using 250 mL of water using US Pharmacopoeia type III. The results are shown in Table 52 below.

(Example 61)
In Example 61, prednisolone tablets containing the formulation described in Example 59 were tested for changes in dissolution with respect to pH, ionic strength, and soaking rate. The evaluated pH was 1.5, 7.5, and pH change.

  In the pH change method, the pH is raised from one dissolution container to the next, and the movement of the dosage form through the gastrointestinal tract is simulated. Initially, the pH is 1.5 for 1 hour. The pH of the second station is 3.5 for an additional 2 hours, after which the third station is 5.5 for an additional 2 hours. Finally, the three final stations are at pH 7.5. The length of time of the three final stations can vary depending on the expected release for that dosage form.

以下の表５５および５６に記載する結果は、実施例５９に従って調製した製剤の溶解プロフィ-ルの標準化した平均値を提供し、ここではｐＨ変化法（０．１Ｍ）で１５および３０ｄｐｍをそれぞれ使用した。

（実施例６２）
実施例６２では、２ｍｇのプレドニゾロンコア組成物を、コア中のプレドニゾロンの量を増加させ、Prosolve SMCC 90の量を減少させ、以下の表５７に記載する製剤を含有させて、実施例２４と同様に調製した：

（実施例６３-６８）
実施例６３-６８では、実施例６２のコア製剤を実施例１１、１２、１３、１４、１５、および１６に従って調製したコーティングで被覆した。それらの実施例の処方を以下の表５８に示す：

米国薬局方器具３を使用し、２５０ｍｌの溶解媒体、１５ｄｐｍで、各製剤について溶解試験を行った。異なる溶解媒体（１）ＤＩ水および（２）ｐＨ変化を使用して２つの溶解法を実施した。表５９はＤＩ水での溶解の結果であり、表６０はｐＨ変化（０．１Ｍ）での溶解の結果である。

データの分析により、得られたデータのlinear fitに基づく遅延時間の概算が可能となる。データは遅延時間が製剤中のガムのレベルに依存して０から８時間まで変化しうることを示している。表６１は実施例、使用したガムの比率（％）、および概算した放出前の遅延時間の概要である。

（実施例６９）
実施例６９では、他の製剤を調製し、米国薬局方器具３型を使用し、２５０ｍｌの溶解媒体を用い、表６２に示す浸漬／分で試験した。 The results are shown in Tables 53 and 54 below. The results showed the dissolution profile of the formulation prepared according to Example 59, with varying pH and ionic strength of the dissolving dissolution medium.

The results listed in Tables 55 and 56 below provide standardized average values for the dissolution profile of the formulation prepared according to Example 59, where 15 and 30 dpm were used with the pH change method (0.1 M), respectively. did.

(Example 62)
In Example 62, 2 mg of prednisolone core composition was added to the formulation described in Table 57 below, increasing the amount of prednisolone in the core, decreasing the amount of Prosolve SMCC 90, and as in Example 24. Prepared in:

(Examples 63-68)
In Examples 63-68, the core formulation of Example 62 was coated with a coating prepared according to Examples 11, 12, 13, 14, 15, and 16. The formulations for these examples are shown in Table 58 below:

Using the US Pharmacopoeia instrument 3, each formulation was tested for dissolution with 250 ml dissolution medium, 15 dpm. Two dissolution methods were performed using different dissolution media (1) DI water and (2) pH change. Table 59 shows the results of dissolution with DI water, and Table 60 shows the results of dissolution with pH change (0.1 M).

By analyzing the data, it is possible to estimate the delay time based on the linear fit of the obtained data. The data show that the lag time can vary from 0 to 8 hours depending on the level of gum in the formulation. Table 61 summarizes the examples, the percentage of gum used, and the estimated delay time before release.

(Example 69)
In Example 69, another formulation was prepared and tested using US Pharmacopoeia instrument type 3 with 250 ml of dissolution medium at the soak / min shown in Table 62.

Specific dissolution media are shown below:
DI water: US Pharmacopoeia Pure water;
pH change or pH change NI (“Ion-Free”): Adjust pH without using ions in the pH change method described in Example 61;
pH change (0.1 M): The pH change method described in Example 61, using salt to bring the ionic strength to 0.1 mol;
pH 7.5: a dissolution medium that is pH 7.5;
pH 7.5 (0.1 M): a dissolution medium having a pH of 7.5 and an ionic strength of 0.1 M;
SGI: A simulation of gastric juice;
Peanut oil pH 7.5: Peanut oil with pH 7.5;
Other dissolution media to be described are readily understood by one of ordinary skill in the art in view of the above (eg, pH 1.5: dissolution medium at pH 1.5, etc.).

コメント：
１．試験９は平均した統合データである。
２．試験１４は平均した統合データである。
３．試験１６は平均した統合データである。
４．試験１７は更なる添加剤として５％ PVPをコーティングに添加した。
５．試験１８は更なる添加剤として１０％ PVPをコーティングに添加した。
６．試験１９は更なる添加剤として５％ MCCをコーティングに添加した。
７．試験２０は更なる添加剤として５％ MCCをコーティングに添加した。
８．試験２１は更なる添加剤として１０％ PEGをコーティングに添加した。
９．試験２２は更なる添加剤として５％ PEGをコーティングに添加した。
１０．試験２３は更なる添加剤として１０％ MCCをコーティングに添加した。
１１．試験２４は更なる添加剤として２０％ MCCをコーティングに添加した。
１２．試験２５は更なる添加剤として５％ PEGをコーティングに添加した。
１３．試験２６は更なる添加剤として５％ PEGをコーティングに添加した。
１４．試験２７は更なる添加剤として１０％ PVPをコーティングに添加した。
１５．試験２８は更なる添加剤として１０％ PVPをコーティングに添加した。
１６．試験２９は更なる添加剤として１０％ PEGをコーティングに添加した。
１７．試験３０は更なる添加剤として５％ PVPをコーティングに添加した。
１８．試験３１は更なる添加剤として１５％ PEGをコーティングに添加した。
１９．試験３２は更なる添加剤として５％ 硫酸カルシウムをコーティングに添加した。
２０．試験３３は更なる添加剤として１０％ 硫酸カルシウムをコーティングに添加した。
２１．試験３４は更なる添加剤として１０％ 硫酸カルシウムをコーティングに添加した。
２２．試験３５は更なる添加剤として３０％ 硫酸カルシウムをコーティングに添加した。
２３．試験３６は更なる添加剤として５％ 硫酸カルシウムをコーティングに添加した。
２４．試験３７は更なる添加剤として１０％ 硫酸カルシウムをコーティングに添加した。
２５．試験３８は更なる添加剤として３０％ 硫酸カルシウムをコーティングに添加した。
２６．試験３９は更なる添加剤として３０％ 硫酸カルシウムをコーティングに添加した。
２７．試験４０は更なる添加剤として１５％ PEGをコーティングに添加した。
２８．試験４１は更なる添加剤として３０５％ 硫酸カルシウムをコーティングに添加した。
２９．試験５４は平均した統合データである。
３０．試験９０は平均した統合データである。
３１．試験９６は２個の錠剤に基づいて行った。
３２．試験９７は２個の錠剤に基づいて行った。
３３．試験９８は３個の錠剤に基づいて行った。
３４．試験９９は３個の錠剤に基づいて行った。
３５．試験１００は６個の錠剤に基づいて行った。
３６．試験１０１は３個の錠剤に基づいて行った。
３７．試験１０２は平均した統合データである。
３８．試験１０３は３個の錠剤に基づいて行った。
３９．試験１０４は３個の錠剤に基づいて行った。
４０．試験１０５は３個の錠剤に基づいて行った。
４１．試験１０６は１２個の錠剤に基づいて行った。
４２．試験１０７は平均した統合データである。
４３．試験１０８は６個の錠剤に基づいて行った。
４４．試験１０９は１２個の錠剤に基づいて行った。
４５．試験１１０は１２個の錠剤に基づいて行った。
４６．試験１１１は３個の錠剤に基づいて行った。
４７．試験１１２は６個の錠剤に基づいて行った。
４８．試験１１３は１２個の錠剤に基づいて行った。
４９．試験１１７は平均した統合データである。
５０．試験１２０は平均した統合データである。
５１．試験１４０は平均した統合データである。
５２．試験１４６は平均した統合データである。
５３．試験１５０は平均した統合データである。 For certain additives described in the comments section, these additives were added to the compression coating prior to coating the core.

comment:
1. Test 9 is the averaged integrated data.
2. Test 14 is averaged integrated data.
3. Test 16 is the average integrated data.
4). Test 17 added 5% PVP to the coating as a further additive.
5. Test 18 added 10% PVP to the coating as a further additive.
6). Test 19 added 5% MCC to the coating as a further additive.
7). Test 20 added 5% MCC to the coating as a further additive.
8). Test 21 added 10% PEG as a further additive to the coating.
9. Test 22 added 5% PEG to the coating as a further additive.
10. Test 23 added 10% MCC to the coating as a further additive.
11. Test 24 added 20% MCC to the coating as a further additive.
12 Test 25 added 5% PEG to the coating as a further additive.
13. Test 26 added 5% PEG to the coating as a further additive.
14 Test 27 added 10% PVP as a further additive to the coating.
15. Test 28 added 10% PVP to the coating as a further additive.
16. Test 29 added 10% PEG to the coating as a further additive.
17. Test 30 added 5% PVP to the coating as a further additive.
18. Test 31 added 15% PEG to the coating as a further additive.
19. Test 32 added 5% calcium sulfate as a further additive to the coating.
20. Test 33 added 10% calcium sulfate to the coating as a further additive.
21. Test 34 added 10% calcium sulfate as a further additive to the coating.
22. Test 35 added 30% calcium sulfate as a further additive to the coating.
23. Test 36 added 5% calcium sulfate as a further additive to the coating.
24. Test 37 added 10% calcium sulfate as a further additive to the coating.
25. Test 38 added 30% calcium sulfate as a further additive to the coating.
26. Test 39 added 30% calcium sulfate as a further additive to the coating.
27. Test 40 added 15% PEG to the coating as a further additive.
28. Test 41 added 305% calcium sulfate to the coating as a further additive.
29. Test 54 is averaged integrated data.
30. Test 90 is averaged integrated data.
31. Test 96 was based on two tablets.
32. Test 97 was based on two tablets.
33. Test 98 was based on 3 tablets.
34. Test 99 was based on 3 tablets.
35. Test 100 was based on 6 tablets.
36. Test 101 was based on 3 tablets.
37. Test 102 is averaged integrated data.
38. Test 103 was based on 3 tablets.
39. Test 104 was based on 3 tablets.
40. Test 105 was based on 3 tablets.
41. Test 106 was based on 12 tablets.
42. Test 107 is averaged integrated data.
43. Test 108 was based on 6 tablets.
44. Test 109 was based on 12 tablets.
45. Test 110 was based on 12 tablets.
46. Test 111 was based on 3 tablets.
47. Test 112 was based on 6 tablets.
48. Test 113 was based on 12 tablets.
49. Test 117 is averaged integrated data.
50. Test 120 is averaged integrated data.
51. Test 140 is averaged integrated data.
52. Test 146 is averaged integrated data.
53. Test 150 is averaged integrated data.

工程：
実施例７０では、実施例２３と同じ工程を使用してコアを調製する。 (Example 70)
An albuterol core composition was prepared with the formulation ingredients listed in Table 63:

Process:
In Example 70, a core is prepared using the same process as Example 23.

工程：
実施例７１では、実施例２３と同じ工程を使用してコアを調製する。 (Example 71)
An albuterol core composition was prepared with the formulation ingredients listed in Table 64:

Process:
In Example 71, the core is prepared using the same process as Example 23.

工程：
実施例７２では、実施例２３と同じ工程を使用してコアを調製する。 (Example 72)
An albuterol core composition was prepared with the formulation ingredients listed in Table 65:

Process:
In Example 72, a core is prepared using the same process as Example 23.

工程：
実施例７３では、実施例２３と同じ工程を使用してコアを調製する。 (Example 73)
An albuterol core composition was prepared with the formulation ingredients listed in Table 66:

Process:
In Example 73, the core is prepared using the same process as Example 23.

工程：
実施例７４では、実施例２３と同じ工程を使用してコアを調製する。 (Example 74)
An albuterol core composition was prepared with the formulation ingredients listed in Table 67:

Process:
In Example 74, the core is prepared using the same process as Example 23.

工程：
実施例７５では、実施例２３と同じ工程を使用し、該当する場合には（表６８参照）フィルムコーティングを施与してコアを調製する。 (Example 75)
An albuterol core composition was prepared with the formulation ingredients listed in Table 68:

Process:
Example 75 uses the same process as Example 23, and where applicable (see Table 68), a film coating is applied to prepare the core.

工程：
実施例７６では、実施例２３と同じ工程を使用し、該当する場合には（表６９参照）フィルムコーティングを施与してコアを調製する。 (Example 76)
An albuterol core composition was prepared with the formulation ingredients listed in Table 69:

Process:
Example 76 uses the same process as Example 23, and where applicable (see Table 69), a film coating is applied to prepare the core.

工程：
実施例７７では、実施例２３と同じ工程を使用し、該当する場合には（表７０参照）フィルムコーティングを施与してコアを調製する。 (Example 77)
An albuterol core composition was prepared with the formulation ingredients listed in Table 70:

Process:
Example 77 uses the same process as Example 23, and where applicable (see Table 70), a film coating is applied to prepare the core.

工程：
実施例７８では、実施例２３と同じ工程を使用し、該当する場合には（表７１参照）フィルムコーティングを施与してコアを調製する。 (Example 78)
An albuterol core composition was prepared with the formulation ingredients listed in Table 71:

Process:
Example 78 uses the same process as Example 23, and where applicable (see Table 71), a film coating is applied to prepare the core.

工程：
実施例７９では、実施例２３と同じ工程を使用し、該当する場合には（表７２参照）フィルムコーティングを施与してコアを調製する。 (Example 79)
An albuterol core composition was prepared with the formulation ingredients listed in Table 72:

Process:
Example 79 uses the same process as Example 23, and where applicable (see Table 72), a film coating is applied to prepare the core.

工程：
実施例８０では、実施例２３と同じ工程を使用し、該当する場合には（表７３参照）フィルムコーティングを施与してコアを調製する。 (Example 80)
An albuterol core composition was prepared with the formulation ingredients listed in Table 73:

Process:
Example 80 uses the same process as Example 23, and when applicable (see Table 73), a film coating is applied to prepare the core.

工程：
実施例８１では、実施例２３と同じ工程を使用し、該当する場合には（表７４参照）フィルムコーティングを施与してコアを調製する。 (Example 81)
An albuterol core composition was prepared with the formulation ingredients listed in Table 74:

Process:
Example 81 uses the same process as Example 23, and where applicable (see Table 74), a film coating is applied to prepare the core.

(Example 82)
In Example 82, other formulations were prepared and tested using 250 U.S. dissolution media and soak / min as shown in Example 75 using US Pharmacopeia device type 3.

持続放出コーティング内の種々のパーセントのガムの効果を以下の表７６に示す：

表７６に示すように、２０％のガムを含有する製剤は３０％または５０％のガムを含有する製剤より速く活性物質を放出した。使用するコーティングが放出速度に影響を与える。実施例８２（ａ）では、コーティング重量および圧縮力が錠剤コア内の活性物質の放出時間および放出速度に与える影響を確認するために遅延放出コーティング製剤を調製した。 A specific dissolution medium is defined as follows:
DI water: US Pharmacopoeia Pure water;
pH Change NI (“Ion Unused”): Adjust pH without using ions with the pH change method described in Example 63;
pH change or change (0.1 M): The pH change method described in Example 63, using salt to bring the ionic strength to 0.1 mol;

The effect of various percent gums in the sustained release coating is shown in Table 76 below:

As shown in Table 76, formulations containing 20% gum released the active substance faster than formulations containing 30% or 50% gum. The coating used affects the release rate. In Example 82 (a), a delayed release coating formulation was prepared to confirm the effect of coating weight and compression force on the release time and release rate of the active substance in the tablet core.

実施例８３では、実施例２３と同じ工程を使用し、フィルムコーティングを施与してコアを調製する。 (Example 83)
A metoprolol core composition was prepared with the formulation ingredients listed in Table 77:

In Example 83, using the same process as Example 23, a film coating is applied to prepare the core.

上に提供した実施例は限定的なものでないことを意図する。本発明の多くの他の変法は当業者に明白であり、添付の特許請求の範囲内であることを意図する。 The core of Example 83 was then compression coated with the compression coating material of the previous example, and the resulting tablets were used for in-vitro dissolution studies as shown in Table 78 below.

The examples provided above are not intended to be limiting. Many other variations of the invention will be apparent to those skilled in the art and are intended to be within the scope of the claims appended hereto.

Claims (28)

A delayed release oral solid dosage composition comprising a core containing a therapeutically effective amount of a drug and a delayed release agent compression coated onto the core, wherein the delayed release agent comprises xanthan gum or locust bean gum The dosage composition as described above, wherein the compression coating delays the release of the drug from the dosage composition from 2 to 18 hours after oral administration of the dosage composition. The delayed release oral solid dosage composition of claim 1, wherein the xanthan gum or locust bean gum is agglomerated with sugar prior to being compression coated onto the core. The delayed release oral solid dosage composition of claim 1, wherein the release of the drug is delayed for at least 4 hours after oral administration of the dosage composition.   The delayed release agent is calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, citric acid The delayed release oral solid dosage composition according to claim 3, further comprising an ionizable gel strength enhancer selected from the group consisting of sodium, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, and mixtures thereof. .   The delayed release oral solid dosage composition according to claim 4, wherein the ionizable gel strength enhancer is calcium sulfate.   The delayed release agent is selected from the group consisting of an anionic surfactant, a cationic surfactant, an amphoteric (amphiphilic / amphophilic) surfactant, and a nonionic surfactant. The delayed release oral solid dosage composition according to claim 1, further comprising an agent.   The delayed release oral solid dosage composition according to claim 1, wherein the delayed release agent further contains a hydrophobic substance. An amount of the hydrophobic substance effective to delay hydration of the gelling agent when administered orally , alkylcellulose, copolymers of acrylic and methacrylic esters, waxes, shellac, zein, hydrogenated vegetable oils, And a delayed release oral solid dosage composition according to claim 7 selected from the group consisting of and mixtures thereof.   8. The delayed release oral solid dosage composition according to claim 7, wherein the hydrophobic substance comprises ethyl cellulose.   The delayed release oral solid dosage composition according to claim 2, wherein the sugar is selected from the group consisting of sucrose, dextrose, lactose, fructose, mannitol, and mixtures thereof.   The delayed release oral solid dosage composition of claim 1, wherein the core further comprises 5-20% by weight of a disintegrant.   12. The delayed release oral solid dosage composition of claim 11, wherein the disintegrant is selected from the group consisting of starch, veegum, cellulose, kaolin, microcrystalline cellulose, cross-linked polyvinyl pyrrolidone, and mixtures thereof.   13. The delayed release oral solid dosage composition of claim 12, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, cross-linked carboxymethyl cellulose, sodium starch glycolate, and mixtures thereof.   The said inner core further comprises an inert diluent selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, mannitol, starch, and mixtures thereof. Delayed release oral solid dosage composition.   The delayed release oral solid dosage composition of claim 1, wherein the core is an immediate release core.   The delayed release oral solid dosage composition of claim 1, wherein the core further comprises a sustained release carrier. The delayed release oral solid dosage composition of claim 1, wherein the xanthan gum is in an amount of 20-80% of the delayed release coating and the locust bean gum is in an amount of 80-20% of the delayed release coating.   The delayed release oral solid dosage composition of claim 1, wherein the coating is 78 to 80 wt% of the total weight of the dosage composition.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of gum in the core and compression coating is from 1: 0.37 to 1: 1.12.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of gum in the core and compression coating is from 1: 0.6 to 1: 1.5.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of gum in the core and compression coating is 1: 0.75.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of core to compression coating is from 1: 2 to 1: 9 by weight.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of core to compression coating is 1: 1 to 1: 5 by weight.   The delayed release oral solid dosage composition of claim 1, wherein the ratio of core to compression coating is from 1: 2 to 1: 3 by weight. A method for preparing an oral solid dosage composition for time treatment of a drug, comprising:
Preparing a core containing a therapeutically effective amount of the drug, and a disintegrant of 5-20% by weight of the core;
Preparing a granule of delayed release agent containing xanthan gum or locust bean gum and compression coating the granule onto the core;
Wherein the compression coating delays the release of the drug from the dosage composition from 2 to 18 hours after oral administration of the dosage composition.   Further, the granule of delayed release agent is prepared by wet granulating one or more natural or synthetic gums with at least one pharmaceutically acceptable additive and drying the resulting granule, the delayed release. 26. The method of claim 25, comprising obtaining agglomerated particles of the agent.   27. The method of claim 26, further comprising granulating the drug, the disintegrant, and a pharmaceutically acceptable inert diluent prior to the compression coating step. A disintegrating agent said disintegrant is incorporated into the core, containing the said core in an effective amount to at least 50% that is released the drug within one hour after the completion of 18 hours from the 2-hour 28. The method of claim 27, wherein: